Publications by authors named "Tej K Pandita"

128 Publications

Gastric cancer in Jammu and Kashmir, India: A review of genetic perspectives.

J Cancer Res Ther 2020 Jan 27. Epub 2020 Jan 27.

Department of Biotechnology, Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir, India.

Gastric Carcinoma (GC) is one of the most common malignancies, which accounts for 6.8% of total cancer population worldwide. In India, the northeastern region has the highest gastric cancer incidence, and the Kashmir Valley has a very high incidence of gastric cancer as compared to other parts of Northern India. It exceeds 40% of total cancers with an incidence rate of 3-6-fold higher than other metro cities of India. Gastric cancer is a heterogeneous disease where most of the cases are sporadic, and <15% are due to obvious familial clustering. The heterogeneous nature of the disease can be associated with differences in genetic makeup of an individual. A better understanding of genetic predisposition toward GC will be helpful in promoting personalized medicine. The aim of this review is to analyze the development and progression of GC and to explore the genetic perspectives of the disease with special emphasis on Jammu and Kashmir, India.
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http://dx.doi.org/10.4103/jcrt.JCRT_12_19DOI Listing
January 2020

Histone Acetyltransferase MOF Orchestrates Outcomes at the Crossroad of Oncogenesis, DNA Damage Response, Proliferation, and Stem Cell Development.

Mol Cell Biol 2020 08 28;40(18). Epub 2020 Aug 28.

The Houston Methodist Research Institute, Houston, Texas, USA

The DNA and protein complex known as chromatin is subject to posttranslational modifications (PTMs) that regulate cellular functions such that PTM dysregulation can lead to disease, including cancer. One critical PTM is acetylation/deacetylation, which is being investigated as a means to develop targeted cancer therapies. The histone acetyltransferase (HAT) family of proteins performs histone acetylation. In humans, MOF (hMOF), a member of the MYST family of HATs, acetylates histone H4 at lysine 16 (H4K16ac). MOF-mediated acetylation plays a critical role in the DNA damage response (DDR) and embryonic stem cell development. Functionally, MOF is found in two distinct complexes: NSL (nonspecific lethal) in humans and MSL (male-specific lethal) in flies. The NSL complex is also able to acetylate additional histone H4 sites. Dysregulation of MOF activity occurs in multiple cancers, including ovarian cancer, medulloblastoma, breast cancer, colorectal cancer, and lung cancer. Bioinformatics analysis of , the gene encoding hMOF, indicated that it is highly overexpressed in kidney tumors as part of a concerted gene coexpression program that can support high levels of chromosome segregation and cell proliferation. The linkage between MOF and tumor proliferation suggests that there are additional functions of MOF that remain to be discovered.
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http://dx.doi.org/10.1128/MCB.00232-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459263PMC
August 2020

Role of HP1β during spermatogenesis and DNA replication.

Chromosoma 2020 12 10;129(3-4):215-226. Epub 2020 Jul 10.

Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, TX, 77030, USA.

Heterochromatin protein 1β (HP1β), encoded by the Cbx1 gene, has been functionally linked to chromatin condensation, transcriptional regulation, and DNA damage repair. Here we report that testis-specific Cbx1 conditional knockout (Cbx1 cKO) impairs male germ cell development in mice. Depletion of HP1β negatively affected sperm maturation and increased seminiferous tubule degeneration in Cbx1 cKO mice. In addition, the spermatogonia have elevated γ-H2AX foci levels as do Cbx1 deficient mouse embryonic fibroblasts (MEFs) as compared to wild-type (WT) control MEFs. The increase in γ-H2AX foci in proliferating Cbx1 cKO cells indicates defective replication-dependent DNA damage repair. Depletion or loss of HP1β from human cells and MEFs increased DNA replication fork stalling and firing of new origins of replication, indicating defective DNA synthesis. Taken together, these results suggest that loss of HP1β in proliferating cells leads to DNA replication defects with associated DNA damage that impact spermatogenesis.
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http://dx.doi.org/10.1007/s00412-020-00739-4DOI Listing
December 2020

Ataxia-telangiectasia mutated interacts with Parkin and induces mitophagy independent of kinase activity. Evidence from mantle cell lymphoma.

Haematologica 2021 Feb 1;106(2):495-512. Epub 2021 Feb 1.

MD Anderson Cancer Center.

Ataxia telangiectasia mutated (ATM), a critical DNA damage sensor with protein kinase activity,is frequently altered in human cancers including mantle cell lymphoma (MCL). Loss of ATM protein is linked to accumulation of nonfunctional mitochondria and defective mitophagy, in both murine thymocytes and in A-T cells. However, the mechanistic role of ATM kinase in cancer cell mitophagy is unknown. Here, we provide evidence that FCCP-induced mitophagy in MCL and other cancer cell lines is dependent on ATM but independent of its kinase function. While Granta-519 MCL cells possess single copy and kinase dead ATM and are resistant to FCCP-induced mitophagy, both Jeko-1 and Mino cells are ATM proficient and induce mitophagy. Stable knockdown of ATM in Jeko-1 and Mino cells conferred resistance to mitophagy and was associated with reduced ATP production, oxygen consumption, and increased mROS. ATM interacts with the E3 ubiquitin ligase Parkin in a kinase-independent manner. Knockdown of ATM in HeLa cells resulted in proteasomal degradation of GFP-Parkin which was rescued by the proteasome inhibitor, MG132 suggesting that ATM-Parkin interaction is important for Parkin stability. Neither loss of ATM kinase activity in primary B cell lymphomas nor inhibition of ATM kinase in MCL, A-T and HeLa cell lines mitigated FCCP or CCCP-induced mitophagy suggesting that ATM kinase activity is dispensable for mitophagy. Malignant B-cell lymphomas without detectable ATM, Parkin, Pink1, and Parkin-Ub ser65 phosphorylation were resistant to mitophagy, providing the first molecular evidence of ATM's role in mitophagy in MCL and other B-cell lymphomas.
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http://dx.doi.org/10.3324/haematol.2019.234385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849759PMC
February 2021

Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability.

J Clin Invest 2020 03;130(3):1431-1445

Rosalind and Morris Goodman Cancer Research Centre and Department of Medicine, McGill University, Montreal, Quebec, Canada.

Epigenetic integrity is critical for many eukaryotic cellular processes. An important question is how different epigenetic regulators control development and influence disease. Lysine acetyltransferase 8 (KAT8) is critical for acetylation of histone H4 at lysine 16 (H4K16), an evolutionarily conserved epigenetic mark. It is unclear what roles KAT8 plays in cerebral development and human disease. Here, we report that cerebrum-specific knockout mice displayed cerebral hypoplasia in the neocortex and hippocampus, along with improper neural stem and progenitor cell (NSPC) development. Mutant cerebrocortical neuroepithelia exhibited faulty proliferation, aberrant neurogenesis, massive apoptosis, and scant H4K16 propionylation. Mutant NSPCs formed poor neurospheres, and pharmacological KAT8 inhibition abolished neurosphere formation. Moreover, we describe KAT8 variants in 9 patients with intellectual disability, seizures, autism, dysmorphisms, and other anomalies. The variants altered chromobarrel and catalytic domains of KAT8, thereby impairing nucleosomal H4K16 acetylation. Valproate was effective for treating epilepsy in at least 2 of the individuals. This study uncovers a critical role of KAT8 in cerebral and NSPC development, identifies 9 individuals with KAT8 variants, and links deficient H4K16 acylation directly to intellectual disability, epilepsy, and other developmental anomalies.
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http://dx.doi.org/10.1172/JCI131145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269600PMC
March 2020

"What's Past is Prologue": Pre-Existing Epigenetic Transcriptional Marks May Also Influence DNA Repair Pathway Choice.

Radiat Res 2019 12 21;192(6):577-578. Epub 2019 Oct 21.

The Houston Methodist Research Institute, Houston, Texas 77030.

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http://dx.doi.org/10.1667/RR15541.1DOI Listing
December 2019

Prion disease is accelerated in mice lacking stress-induced heat shock protein 70 (HSP70).

J Biol Chem 2019 09 18;294(37):13619-13628. Epub 2019 Jul 18.

Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, University of Texas McGovern Medical School, Houston, Texas 77030

Prion diseases are a group of incurable neurodegenerative disorders that affect humans and animals via infection with proteinaceous particles called prions. Prions are composed of PrP, a misfolded version of the cellular prion protein (PrP). During disease progression, PrP replicates by interacting with PrP and inducing its conversion to PrP As PrP accumulates, cellular stress mechanisms are activated to maintain cellular proteostasis, including increased protein chaperone levels. However, the exact roles of several of these chaperones remain unclear. Here, using various methodologies to monitor prion replication ( protein misfolding cyclic amplification and cellular and animal infectivity bioassays), we studied the potential role of the molecular chaperone heat shock protein 70 (HSP70) in prion replication and Our results indicated that pharmacological induction of the heat shock response in cells chronically infected with prions significantly decreased PrP accumulation. We also found that HSP70 alters prion replication More importantly, prion infection of mice lacking the genes encoding stress-induced HSP70 exhibited accelerated prion disease progression compared with WT mice. In parallel with HSP70 being known to respond to endogenous and exogenous stressors such as heat, infection, toxicants, and ischemia, our results indicate that HSP70 may also play an important role in suppressing or delaying prion disease progression, opening opportunities for therapeutic intervention.
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http://dx.doi.org/10.1074/jbc.RA118.006186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746463PMC
September 2019

Pre-existing H4K16ac levels in euchromatin drive DNA repair by homologous recombination in S-phase.

Commun Biol 2019 5;2:253. Epub 2019 Jul 5.

1Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, TX 77030 USA.

The homologous recombination (HR) repair pathway maintains genetic integrity after DNA double-strand break (DSB) damage and is particularly crucial for maintaining fidelity of expressed genes. Histone H4 acetylation on lysine 16 (H4K16ac) is associated with transcription, but how pre-existing H4K16ac directly affects DSB repair is not known. To answer this question, we used CRISPR/Cas9 technology to introduce I-SceI sites, or repair pathway reporter cassettes, at defined locations within gene-rich (high H4K16ac/euchromatin) and gene-poor (low H4K16ac/heterochromatin) regions. The frequency of DSB repair by HR is higher in gene-rich regions. Interestingly, artificially targeting H4K16ac at specific locations using gRNA/dCas9-MOF increases HR frequency in euchromatin. Finally, inhibition/depletion of RNA polymerase II or Cockayne syndrome B protein leads to decreased recruitment of HR factors at DSBs. These results indicate that the pre-existing H4K16ac status at specific locations directly influences the repair of local DNA breaks, favoring HR in part through the transcription machinery.
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http://dx.doi.org/10.1038/s42003-019-0498-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611875PMC
May 2020

The BRUCE-ATR Signaling Axis Is Required for Accurate DNA Replication and Suppression of Liver Cancer Development.

Hepatology 2019 06 13;69(6):2608-2622. Epub 2019 Mar 13.

Department of Cancer and Cell Biology, University of Cincinnati, Cincinnati, OH.

Replication fork stability during DNA replication is vital for maintenance of genomic stability and suppression of cancer development in mammals. ATR (ataxia-telangiectasia mutated [ATM] and RAD3-related) is a master regulatory kinase that activates the replication stress response to overcome replication barriers. Although many downstream effectors of ATR have been established, the upstream regulators of ATR and the effect of such regulation on liver cancer remain unclear. The ubiquitin conjugase BRUCE (BIR Repeat containing Ubiquitin-Conjugating Enzyme) is a guardian of chromosome integrity and activator of ATM signaling, which promotes DNA double-strand break repair through homologous recombination. Here we demonstrate the functions for BRUCE in ATR activation in vitro and liver tumor suppression in vivo. BRUCE is recruited to induced DNA damage sites. Depletion of BRUCE inhibited multiple ATR-dependent signaling events during replication stress, including activation of ATR itself, phosphorylation of its downstream targets CHK1 and RPA, and the mono-ubiquitination of FANCD2. Consequently, BRUCE deficiency resulted in stalled DNA replication forks and increased firing of new replication origins. The in vivo impact of BRUCE loss on liver tumorigenesis was determined using the hepatocellular carcinoma model induced by genotoxin diethylnitrosamine. Liver-specific knockout of murine Bruce impaired ATR activation and exacerbated inflammation, fibrosis and hepatocellular carcinoma, which exhibited a trabecular architecture, closely resembling human hepatocellular carcinoma (HCC). In humans, the clinical relevance of BRUCE down-regulation in liver disease was found in hepatitis, cirrhosis, and HCC specimens, and deleterious somatic mutations of the Bruce gene was found in human hepatocellular carcinoma in the Cancer Genome Atlas database. Conclusion: These findings establish a BRUCE-ATR signaling axis in accurate DNA replication and suppression of liver cancer in mice and humans and provides a clinically relevant HCC mouse model.
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http://dx.doi.org/10.1002/hep.30529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541504PMC
June 2019

Genetic and Pharmacological Targeting of Heat Shock Protein 70 in the Mouse Amygdala-Kindling Model.

ACS Chem Neurosci 2019 03 16;10(3):1434-1444. Epub 2018 Nov 16.

Institute of Pharmacology, Toxicology, and Pharmacy , Ludwig-Maximilians-University Munich , Koeniginstraße 16 , D-80539 Munich , Germany.

Inflammatory responses involving Toll-like receptor signaling represent a key factor contributing to epileptogenesis. Thus, it is of particular interest to explore the relevance of toll-like receptor ligands and modulators, such as heat shock protein 70 (HSP70). Motivated by recent findings demonstrating an upregulation of HSP70 in a model of epileptogenesis, we analyzed the consequences of genetic and pharmacological targeting of HSP70 expression in a mouse kindling paradigm. Lack of inducible HSP70 resulted in increased prekindling seizure thresholds. However, at threshold stimulation the deficiency-promoted seizure spread, as indicated by an increased seizure severity. Subsequent kindling stimulations elicited more severe seizures in knockout mice, whereas endogenous termination of seizure activity remained unaffected with duration of behavioral and electrographic seizure activity comparable to that of wild-type mice. Interestingly, HSP70 deficiency resulted in enhanced microglia activation in the CA1 region. Next, we assessed a pharmacological targeting approach aiming to promote HSP70 expression. Celastrol treatment had no impact on kindling progression but reduced postkindling seizure thresholds and enhanced microglia activation in CA1 and CA3. In conclusion, the findings from HSP70-knockout mice support a protective role of HSP70 with an effect on microglia activation and spread of seizure activity. Unexpectedly, celastrol administration resulted in detrimental consequences. These findings should be considered as a warning about the general safety of celastrol as a drug candidate. The impact of pathophysiological mechanisms on the quality of celastrol effects requires comprehensive future studies exploring influencing factors. Moreover, alternate strategies to increase HSP70 expression should be further developed and validated.
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http://dx.doi.org/10.1021/acschemneuro.8b00475DOI Listing
March 2019

Correction: A homozygous FANCM frameshift pathogenic variant causes male infertility.

Genet Med 2019 01;21(1):266

Hefei National Laboratory for Physical Sciences at Microscale, The First Affiliated Hospital of USTC, USTC-SJH Joint Center for Human Reproduction and Genetics, The CAS Key Laboratory of Innate Immunity and Chronic Diseases, School of Life Sciences, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center of Genetics and Development, University of Science and Technology of China, Hefei 230027, China.

Hao Win, Hui Ma and Sajjad Hussain were incorrectly affiliated to 'Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, TX 77030 USA'. These authors should only have been affiliated to 'Hefei National Laboratory for Physical Sciences at Microscale, The First Affiliated Hospital of USTC, USTC-SJH Joint Center for Human Reproduction and Genetics, The CAS Key Laboratory of Innate Immunity and Chronic Diseases, School of Life Sciences, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center of Genetics and Development, University of Science and Technology of China, Hefei 230027, China'. They were also not noted as contributing equally to the paper. Both these errors have now been corrected in the PDF and HTML versions of the paper.
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http://dx.doi.org/10.1038/s41436-018-0127-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752282PMC
January 2019

The small heat shock protein HSPB1 protects mice from sepsis.

Sci Rep 2018 08 21;8(1):12493. Epub 2018 Aug 21.

Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, GA, Georgia.

In vitro studies have implicated the small heat shock protein HSPB1 in a range of physiological functions. However, its in vivo relevance is unclear as the phenotype of unstressed HSPB1 mice is unremarkable. To determine the impact of HSPB1 in injury, HSPB1 and wild type (WT) mice were subjected to cecal ligation and puncture, a model of polymicrobial sepsis. Ten-day mortality was significantly higher in HSPB1 mice following the onset of sepsis (65% vs. 35%). Ex vivo mechanical testing revealed that common carotid arteries from HSPB1 mice were more compliant than those in WT mice over pressures of 50-120 mm Hg. Septic HSPB1 mice also had increased peritoneal levels of IFN-γ and decreased systemic levels of IL-6 and KC. There were no differences in frequency of either splenic CD4 or CD8 T cells, nor were there differences in apoptosis in either cell type. However, splenic CD4 T cells and CD8 T cells from HSPB1 mice produced significantly less TNF and IL-2 following ex vivo stimulation. Systemic and local bacterial burden was similar in HSPB1 and WT mice. Thus while HSPB1 mice are uncompromised under basal conditions, HSPB1 has a critical function in vivo in sepsis, potentially mediated through alterations in arterial compliance and the immune response.
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http://dx.doi.org/10.1038/s41598-018-30752-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104051PMC
August 2018

Complete Local and Abscopal Responses from a Combination of Radiation and Nivolumab in Refractory Hodgkin's Lymphoma.

Radiat Res 2018 09 27;190(3):322-329. Epub 2018 Jun 27.

Department of a   Internal Medicine, Houston Methodist Research Institute, Houston, Texas 77030.

Until recently, patients with relapsed Hodgkin's lymphoma after brentuximab vedotin (Bv) treatments had poor treatment outcomes. Checkpoint inhibitors such as nivolumab and pembrolizumab that bind to and inhibit programmed cell death protein-1 (PD-1), have demonstrated an overall response rate of 70% in Hodgkin's lymphoma patients; however, complete response is still low at 20% with median progression-free survival of 14 months. There are ongoing clinical studies to seek out synergistic combinations, with the goal of improving the complete response rates for the cure of Hodgkin's lymphoma. Although radiotherapy has a limited survival benefit in such refractory patients, several preclinical models and anecdotal clinical evidence have suggested that combining local tumor irradiation with checkpoint inhibitors can produce systemic regression of distant tumors, an abscopal effect. Most of these reported studies on the response with local conformal radiotherapy and checkpoint inhibitors in combination with the anti-cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) antibody-ipilimumab are in melanoma. Here we report in our case series that the checkpoint inhibitors that block CTLA4 and B7-homolog 1 (B7-H1) or PD-1 in preclinical radiotherapy models have shown an increased the rate of tumor regression. Our case series demonstrates that combining local irradiation with anti-PD-1 checkpoint blockade treatment is feasible and synergistic in refractory Hodgkin's lymphoma. Correlative studies also suggest that the expression of programmed death-ligand 1 (PD-L1), DNA damage response and mutational tumor burden can be used as potential biomarkers for treatment response.
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http://dx.doi.org/10.1667/RR15048.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135239PMC
September 2018

A homozygous FANCM frameshift pathogenic variant causes male infertility.

Genet Med 2019 01 12;21(1):62-70. Epub 2018 Jun 12.

Hefei National Laboratory for Physical Sciences at Microscale, The First Affiliated Hospital of USTC, USTC-SJH Joint Center for Human Reproduction and Genetics, The CAS Key Laboratory of Innate Immunity and Chronic Diseases, School of Life Sciences, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center of Genetics and Development, University of Science and Technology of China, Hefei, 230027, China.

Purpose: Fanconi anemia (FA) genes play important roles in spermatogenesis. In mice, disruption of Fancm impairs male fertility and testicular integrity, but whether FANCM pathogenic variants (PV) similarly affect fertility in men is unknown. Here we characterize a Pakistani family having three infertile brothers, two manifesting oligoasthenospermia and one exhibiting azoospermia, born to first-cousin parents. A homozygous PV in FANCM (c.1946_1958del, p.P648Lfs*16) was found cosegregating with male infertility. Our objective is to validate that FANCM p.P648Lfs*16 is the PV causing infertility in this family.

Methods: Exome and Sanger sequencing were used for PV screening. DNA interstrand crosslink (ICL) sensitivity was assessed in lymphocytes from patients. A mouse model carrying a PV nearly equivalent to that in the patients (Fancm) was generated, followed by functional analysis in spermatogenesis.

Results: The loss-of-function FANCM PV increased ICL sensitivity in lymphocytes of patients and Fancm spermatogonia. Adult Fancm mice showed spermatogenic failure, with germ cell loss in 50.2% of testicular tubules and round-spermatid maturation arrest in 43.5% of tubules. In addition, neither bone marrow failure nor cancer/tumor was detected in all the patients or adult Fancm mice.

Conclusion: These findings revealed male infertility to be a novel phenotype of human patients with a biallelic FANCM PV.
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http://dx.doi.org/10.1038/s41436-018-0015-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752308PMC
January 2019

SMARCAD1 Phosphorylation and Ubiquitination Are Required for Resection during DNA Double-Strand Break Repair.

iScience 2018 04;2:123-135

Department of Radiation Oncology, Houston Methodist Cancer Center, The Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA. Electronic address:

The chromatin remodeling factor SMARCAD1, an SWI/SNF ATPase family member, has a role in 5' end resection at DNA double-strand breaks (DSBs) to produce single-strand DNA (ssDNA), a critical step for subsequent checkpoint and repair factor loading to remove DNA damage. However, the mechanistic details of SMARCAD1 coupling to the DNA damage response and repair pathways remains unknown. Here we report that SMARCAD1 is recruited to DNA DSBs through an ATM-dependent process. Depletion of SMARCAD1 reduces ionizing radiation (IR)-induced repairosome foci formation and DSB repair by homologous recombination (HR). IR induces SMARCAD1 phosphorylation at a conserved T906 by ATM kinase, a modification essential for SMARCAD1 recruitment to DSBs. Interestingly, T906 phosphorylation is also important for SMARCAD1 ubiquitination by RING1 at K905. Both these post-translational modifications are critical for regulating the role of SMARCAD1 in DNA end resection, HR-mediated repair, and cell survival after DNA damage.
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http://dx.doi.org/10.1016/j.isci.2018.03.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993204PMC
April 2018

MOF influences meiotic expansion of H2AX phosphorylation and spermatogenesis in mice.

PLoS Genet 2018 05 24;14(5):e1007300. Epub 2018 May 24.

Hefei National Laboratory for Physical Sciences at the Microscale, USTC-SJH Joint Center for Human Reproduction and Genetics, The CAS Key Laboratory of Innate Immunity and Chronic Diseases, School of Life Sciences, CAS Center for Excellence in Molecular Cell Science, University of Science and Technology of China (USTC), Collaborative Innovation Center of Genetics and Development, Hefei, Anhui, China.

Three waves of H2AX phosphorylation (γH2AX) have been observed in male meiotic prophase I: the first is ATM-dependent and occurs at leptonema, while the second and third are ATR-dependent, occuring at zygonema and pachynema, respectively. The third wave of H2AX phosphorylation marks and silences unsynapsed chromosomes. Little is known about H2AX phosphorylation expands to chromatin-wide regions in spermatocytes. Here, we report that histone acetyltransferase (HAT) MOF is involved in all three waves of H2AX phosphorylation expansion. Germ cell-specific deletion of Mof in spermatocytes by Stra8-Cre (Mof cKO) caused global loss of H4K16ac. In leptotene and zygotene spermatocytes of cKO mice, the γH2AX signals were observed only along the chromosomal axes, and chromatin-wide H2AX phosphorylation was lost. In almost 40% of early-mid pachytene spermatocytes from Mof cKO mice, γH2AX and MDC1 were detected along the unsynapsed axes of the sex chromosomes, but failed to expand, which consequently caused meiotic sex chromosome inactivation (MSCI) failure. Furthermore, though RAD51 was proficiently recruited to double-strand break (DSB) sites, defects in DSB repair and crossover formation were observed in Mof cKO spermatocytes, indicating that MOF facilitates meiotic DSB repair after RAD51 recruitment. We propose that MOF regulates male meiosis and is involved in the expansion of all three waves of H2AX phosphorylation from the leptotene to pachytene stages, initiated by ATM and ATR, respectively.
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http://dx.doi.org/10.1371/journal.pgen.1007300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019819PMC
May 2018

Harnessing and Optimizing the Interplay between Immunotherapy and Radiotherapy to Improve Survival Outcomes.

Mol Cancer Res 2018 08 28;16(8):1209-1214. Epub 2018 Mar 28.

Department of Radiation Oncology, the Houston Methodist Research Institute, Weil Cornell Medical College, Houston, Texas.

In the past, radiotherapy was primarily used to control local disease, but recent technological advances in accurate, high-dose ionizing radiation (IR) delivery have not only increased local tumor control but in some cases reduced metastatic burden. These "off target" therapeutic effects of IR at nonirradiated tumor sites, also known as abscopal effects, are thought to be mediated by tumor antigen-primed T cells that travel to metastatic sites and promote tumor regression. Similarly, early indications reveal that IR in combination with immune checkpoint inhibitors, such as ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1), can provide superior therapeutic responses. These observations suggest that local radiotherapy results in altered gene expression, exposure of new antigens, or cell death that can interact with immunotherapy. As such, radiotherapy enhancement of immune responses offers a promising synergy with the potential for substantial clinical benefit. This review focuses on the biology that underlies the mechanisms for the interaction between radiation-induced tumor cell death and enhanced immunologic response. .
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http://dx.doi.org/10.1158/1541-7786.MCR-17-0743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072560PMC
August 2018

β1-Integrin Impacts Rad51 Stability and DNA Double-Strand Break Repair by Homologous Recombination.

Mol Cell Biol 2018 05 16;38(9). Epub 2018 Apr 16.

Department of Radiation Oncology, Weill Cornell Medical College, The Houston Methodist Research Institute, Houston, Texas, USA

The molecular mechanisms underlying resistance to radiotherapy in breast cancer cells remain elusive. Previously, we reported that elevated β1-integrin is associated with enhanced breast cancer cell survival postirradiation, but how β1-integrin conferred radioresistance was unclear. Ionizing radiation (IR) induced cell killing correlates with the efficiency of DNA double-strand break (DSB) repair, and we found that nonmalignant breast epithelial (S1) cells with low β1-integrin expression have a higher frequency of S-phase-specific IR-induced chromosomal aberrations than the derivative malignant breast (T4-2) cells with high β1-integrin expression. In addition, there was an increased frequency of IR-induced homologous recombination (HR) repairosome focus formation in T4-2 cells compared with that of S1 cells. Cellular levels of Rad51 in T4-2 cells, a critical factor in HR-mediated DSB repair, were significantly higher. Blocking or depleting β1-integrin activity in T4-2 cells reduced Rad51 levels, while ectopic expression of β1-integrin in S1 cells correspondingly increased Rad51 levels, suggesting that Rad51 is regulated by β1-integrin. The low level of Rad51 protein in S1 cells was found to be due to rapid degradation by the ubiquitin proteasome pathway (UPP). Furthermore, the E3 ubiquitin ligase RING1 was highly upregulated in S1 cells compared to T4-2 cells. Ectopic β1-integrin expression in S1 cells reduced RING1 levels and increased Rad51 accumulation. In contrast, β1-integrin depletion in T4-2 cells significantly increased RING1 protein levels and potentiated Rad51 ubiquitination. These data suggest for the first time that elevated levels of the extracellular matrix receptor β1-integrin can increase tumor cell radioresistance by decreasing Rad51 degradation through a RING1-mediated proteasomal pathway.
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http://dx.doi.org/10.1128/MCB.00672-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902589PMC
May 2018

MOF Suppresses Replication Stress and Contributes to Resolution of Stalled Replication Forks.

Mol Cell Biol 2018 03 27;38(6). Epub 2018 Feb 27.

Department of Radiation Oncology, Weill Cornell Medical College, The Houston Methodist Research Institute, Houston, Texas, USA

The human MOF (hMOF) protein belongs to the MYST family of histone acetyltransferases and plays a critical role in transcription and the DNA damage response. MOF is essential for cell proliferation; however, its role during replication and replicative stress is unknown. Here we demonstrate that cells depleted of MOF and under replicative stress induced by cisplatin, hydroxyurea, or camptothecin have reduced survival, a higher frequency of S-phase-specific chromosome damage, and increased R-loop formation. MOF depletion decreased replication fork speed and, when combined with replicative stress, also increased stalled replication forks as well as new origin firing. MOF interacted with PCNA, a key coordinator of replication and repair machinery at replication forks, and affected its ubiquitination and recruitment to the DNA damage site. Depletion of MOF, therefore, compromised the DNA damage repair response as evidenced by decreased Mre11, RPA70, Rad51, and PCNA focus formation, reduced DNA end resection, and decreased CHK1 phosphorylation in cells after exposure to hydroxyurea or cisplatin. These results support the argument that MOF plays an important role in suppressing replication stress induced by genotoxic agents at several stages during the DNA damage response.
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http://dx.doi.org/10.1128/MCB.00484-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829482PMC
March 2018

Cross Talk between Radiation and Immunotherapy: The Twain Shall Meet.

Radiat Res 2018 03 20;189(3):219-224. Epub 2017 Dec 20.

b   Department of Radiation Oncology, The Houston Methodist Research Institute, Weil Cornell Medical College, Houston Texas 77030.

There has been increased interest in the immune stimulatory properties of ionizing radiation based on several preclinical models and recently completed clinical studies performed in combination with checkpoint inhibitors. This is a paradigm shift in that it considers the role of radiation beyond its direct cytotoxic effects, however, the factors that promote or limit radiation-induced immunogenicity are still unclear. Here we review the role of radiation in modulating the various aspects of the tumor immune microenvironment and discuss in particular the direct effects of radiation on the DNA damage response and its immediate consequences to neighboring cells. The latter "danger response" in particular can enhance recruitment of dendritic and macrophage cells to the tumor microenvironment, which in turn can activate or diminish subsequent T-cell priming. Identification of the critical factors that modulate the interaction between radiation-induced cell damage and the immune system will allow for rational combinational therapy design and the development of biomarkers that predict effective immune responses.
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http://dx.doi.org/10.1667/RR14941.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858718PMC
March 2018

Deletion in Head and Neck Cancer Cells Is Associated with CDK2 Activation, Replication Stress, and Vulnerability to CHK1 Inhibition.

Cancer Res 2018 02 11;78(3):781-797. Epub 2017 Dec 11.

Department of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas.

Checkpoint kinase inhibitors (CHKi) exhibit striking single-agent activity in certain tumors, but the mechanisms accounting for hypersensitivity are poorly understood. We screened a panel of 49 established human head and neck squamous cell carcinoma (HNSCC) cell lines and report that nearly 20% are hypersensitive to CHKi monotherapy. Hypersensitive cells underwent early S-phase arrest at drug doses sufficient to inhibit greater than 90% of CHK1 activity. Reduced rate of DNA replication fork progression and chromosomal shattering were also observed, suggesting replication stress as a root causative factor in CHKi hypersensitivity. To explore genomic underpinnings of CHKi hypersensitivity, comparative genomic analysis was performed between hypersensitive cells and cells categorized as least sensitive because they showed drug IC value greater than the cell panel median and lacked early S-phase arrest. Novel association between copy number loss, CDK2 activation, replication stress, and hypersensitivity of HNSCC cells to CHKi monotherapy was found. Restoring p16 in cell lines harboring genomic deletions alleviated CDK2 activation and replication stress, attenuating CHKi hypersensitivity. Taken together, our results suggest a biomarker-driven strategy for selecting HNSCC patients who may benefit the most from CHKi therapy. These results suggest a biomarker-driven strategy for selecting HNSCC patients who may benefit the most from therapy with CHK inhibitors. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-2802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811346PMC
February 2018

HER2 Confers Resistance to Foretinib Inhibition of MET-Amplified Esophageal Adenocarcinoma Cells.

Ann Thorac Surg 2018 Feb 7;105(2):363-370. Epub 2017 Dec 7.

Department of Thoracic and Cardiovascular Surgery, MD Anderson Cancer Center, Houston, Texas.

Background: Recent genomic studies indicated that esophageal adenocarcinoma (EAC) is driven by amplification of c-MET or HER2 or both in a subset of patients. We studied the effect of MET targeting by the small molecule inhibitor foretinib in EAC cells and the interplay between MET and HER2 signaling.

Methods: We measured the expression levels and phosphorylation status of MET and HER2 proteins in EAC cell lines using Western blot analysis. The expression levels of MET and HER2 were manipulated by transfecting cells with specific siRNA or a plasmid expressing HER2. The small molecule inhibitors of c-MET and ERBB1/2 (foretinib and lapatinib, respectively) were tested for effect on growth, apoptosis, and downstream signaling pathways of EAC cells as single agents or in combination. The response to inhibitors was correlated to the levels of MET, HER2 expression, and amplification status.

Results: Foretinib inhibits phosphorylation of MET, which correlated with reduced EAC cell growth and inhibition of AKT and ERK phosphorylation. Cell growth inhibition by foretinib is most profound in the ESO51 cell line, which has MET gene amplification and overexpression. Inhibition of MET signaling by foretinib or siRNA-specific knock down of MET expression induces apoptosis in ESO51 cells. Ectopic expression of HER2 reduces foretinib-mediated growth inhibition and downstream ERK phosphorylation in ESO51-HER2 cells. The EAC OE33 cell line, with amplification and overexpression of both MET and HER2, demonstrated reduced sensitivity to foretinib or lapatinib and had a transient effect on downstream inhibition of phosphorylated AKT and ERK (p-AKT, p-ERK). The coadministration of foretinib and lapatinib effectively blocked both MET and HER2 signaling through the p-AKT and p-ERK pathways, dramatically inhibited growth, and induced apoptosis to overcome single-agent resistance in OE33 cells.

Conclusions: The mechanism for foretinib growth inhibition in MET-amplified EAC tumor cells is demonstrated. The interplay of dual MET/HER2 overexpression in the AKT and ERK pathways for esophageal cancer is described. Therefore, combination therapy could be a novel strategy for EAC with amplification of both MET and HER2.
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http://dx.doi.org/10.1016/j.athoracsur.2017.09.003DOI Listing
February 2018

Differentiation of Human Induced Pluripotent or Embryonic Stem Cells Decreases the DNA Damage Repair by Homologous Recombination.

Stem Cell Reports 2017 11 2;9(5):1660-1674. Epub 2017 Nov 2.

Department of Radiation Oncology, Weill Cornell Medical College, The Houston Methodist Hospital Research Institute, Houston, TX 77030, USA. Electronic address:

The nitric oxide (NO)-cyclic GMP pathway contributes to human stem cell differentiation, but NO free radical production can also damage DNA, necessitating a robust DNA damage response (DDR) to ensure cell survival. How the DDR is affected by differentiation is unclear. Differentiation of stem cells, either inducible pluripotent or embryonic derived, increased residual DNA damage as determined by γ-H2AX and 53BP1 foci, with increased S-phase-specific chromosomal aberration after exposure to DNA-damaging agents, suggesting reduced homologous recombination (HR) repair as supported by the observation of decreased HR-related repair factor foci formation (RAD51 and BRCA1). Differentiated cells also had relatively increased fork stalling and R-loop formation after DNA replication stress. Treatment with NO donor (NOC-18), which causes stem cell differentiation has no effect on double-strand break (DSB) repair by non-homologous end-joining but reduced DSB repair by HR. Present studies suggest that DNA repair by HR is impaired in differentiated cells.
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http://dx.doi.org/10.1016/j.stemcr.2017.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831054PMC
November 2017

Erratum: miR-15a/miR-16 down-regulates BMI1, impacting Ub-H2A mediated DNA repair and breast cancer cell sensitivity to doxorubicin.

Sci Rep 2017 10 10;7(1):12932. Epub 2017 Oct 10.

Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, Telangana State, 500007, India.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-017-12314-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635132PMC
October 2017

Transcription regulation of CDKN1A (p21/CIP1/WAF1) by TRF2 is epigenetically controlled through the REST repressor complex.

Sci Rep 2017 09 14;7(1):11541. Epub 2017 Sep 14.

Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi, 110025, India.

We observed extra-telomeric binding of the telomere repeat binding factor TRF2 within the promoter of the cyclin-dependent kinase CDKNIA (p21/CIP1/WAF1). This result in TRF2 induced transcription repression of p21. Interestingly, p21 repression was through engagement of the REST-coREST-LSD1-repressor complex and altered histone marks at the p21 promoter in a TRF2-dependent fashion. Furthermore, mutational analysis shows p21 repression requires interaction of TRF2 with a p21 promoter G-quadruplex. Physiologically, TRF2-mediated p21 repression attenuated drug-induced activation of cellular DNA damage response by evading G2/M arrest in cancer cells. Together these reveal for the first time role of TRF2 in REST- repressor complex mediated transcription repression.
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http://dx.doi.org/10.1038/s41598-017-11177-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599563PMC
September 2017

miR-15a/miR-16 down-regulates BMI1, impacting Ub-H2A mediated DNA repair and breast cancer cell sensitivity to doxorubicin.

Sci Rep 2017 06 27;7(1):4263. Epub 2017 Jun 27.

Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, Telangana State, 500007, India.

The B-lymphoma Moloney murine leukemia virus insertion region-1 protein (BMI1) acts as an oncogene in various cancers, including breast cancer. Recent evidence suggests that BMI1 is rapidly recruited to sites of DNA double strand breaks where it facilitates histone H2A ubiquitination and DNA double strand break repair by homologous recombination. Here we show that miR-15a and miR-16 expression is decreased during the initial period after DNA damage where it would otherwise down-regulate BMI1, impairing DNA repair. Elevated miR-15a and miR-16 levels down-regulated BMI1 and other polycomb group proteins like RING1A, RING1B, EZH2 and also altered the expression of proteins associated with the BMI1 dependent ubiquitination pathway. Antagonizing the expression of miR-15a and miR-16, enhanced BMI1 protein levels and increased DNA repair. Further, overexpression of miR-15a and miR-16 sensitized breast cancer cells to DNA damage induced by the chemotherapeutic drug doxorubicin. Our results suggest that miR-15a and miR-16 mediate the down-regulation of BMI1, which impedes DNA repair while elevated levels can sensitize breast cancer cells to doxorubicin leading to apoptotic cell death. This data identifies a new target for manipulating DNA damage response that could impact the development of improved therapeutics for breast cancer.
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http://dx.doi.org/10.1038/s41598-017-02800-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487337PMC
June 2017

Histone acetyltransferase KAT8 is essential for mouse oocyte development by regulating reactive oxygen species levels.

Development 2017 06 15;144(12):2165-2174. Epub 2017 May 15.

Molecular and Cell Genetics Laboratory, The CAS Key Laboratory of Innate Immunity and Chronic Diseases, Hefei National Laboratory for Physical Sciences at Microscale, School of Life Sciences, CAS Center for Excellence in Molecular Cell Science, University of Science and Technology of China, Collaborative Innovation Center of Genetics and Development, Collaborative Innovation Center for Cancer Medicine, Hefei, Anhui 230027, China

Proper oocyte development is crucial for female fertility and requires timely and accurate control of gene expression. K (lysine) acetyltransferase 8 (KAT8), an important component of the X chromosome dosage compensation system in , regulates gene activity by acetylating histone H4 preferentially at lysine 16. To explore the function of KAT8 during mouse oocyte development, we crossed mice with mice to specifically delete in oocytes. Oocyte deletion resulted in female infertility, with follicle development failure in the secondary and preantral follicle stages. RNA-seq analysis revealed that deficiency in oocytes results in significant downregulation of antioxidant genes, with a consequent increase in reactive oxygen species. Intraperitoneal injection of the antioxidant N-acetylcysteine rescued defective follicle and oocyte development resulting from deficiency. Chromatin immunoprecipitation assays indicated that KAT8 regulates antioxidant gene expression by direct binding to promoter regions. Taken together, our findings demonstrate that KAT8 is essential for female fertility by regulating antioxidant gene expression and identify KAT8 as the first histone acetyltransferase with an essential function in oogenesis.
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http://dx.doi.org/10.1242/dev.149518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482993PMC
June 2017

Aurora kinase B dependent phosphorylation of 53BP1 is required for resolving merotelic kinetochore-microtubule attachment errors during mitosis.

Oncotarget 2017 Jul;8(30):48671-48687

Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX, USA.

Defects in resolving kinetochore-microtubule attachment mistakes during mitosis is linked to chromosome instability associated with carcinogenesis as well as resistance to cancer therapy. Here we report for the first time that tumor suppressor p53-binding protein 1 (53BP1) is phosphorylated at serine 1342 (S1342) by Aurora kinase B both in vitro and in human cells, which is required for optimal recruitment of 53BP1 at kinetochores. Furthermore, 53BP1 staining normally localized on the outer kinetochore, extended to the whole kinetochore when it is merotelically-attached, in concert with mitotic centromere-associated kinesin. Kinetochore-binding of pS1342-53BP1 is essential for efficient resolving of merotelic attachment, a spontaneous kinetochore-microtubule connection error that usually causes aneuploidy. Consistently, loss of 53BP1 results in significant increase in lagging chromosome events, micronuclei formation and aneuploidy, due to the unresolved merotely in both cancer and primary cells, which is prevented by ectopic wild type 53BP1 but not by the nonphophorylable S1342A mutant. We thus document a novel DNA damage-independent function of 53BP1 in maintaining faithful chromosome segregation during mitosis.
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http://dx.doi.org/10.18632/oncotarget.16225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564716PMC
July 2017

Ssb1 and Ssb2 cooperate to regulate mouse hematopoietic stem and progenitor cells by resolving replicative stress.

Blood 2017 05 7;129(18):2479-2492. Epub 2017 Mar 7.

QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.

Hematopoietic stem and progenitor cells (HSPCs) are vulnerable to endogenous damage and defects in DNA repair can limit their function. The 2 single-stranded DNA (ssDNA) binding proteins SSB1 and SSB2 are crucial regulators of the DNA damage response; however, their overlapping roles during normal physiology are incompletely understood. We generated mice in which both and were constitutively or conditionally deleted. Constitutive double knockout (DKO) caused early embryonic lethality, whereas conditional double knockout (cDKO) in adult mice resulted in acute lethality due to bone marrow failure and intestinal atrophy featuring stem and progenitor cell depletion, a phenotype unexpected from the previously reported single knockout models of or Mechanistically, cDKO HSPCs showed altered replication fork dynamics, massive accumulation of DNA damage, genome-wide double-strand breaks enriched at Ssb-binding regions and CpG islands, together with the accumulation of -loops and cytosolic ssDNA. Transcriptional profiling of cDKO HSPCs revealed the activation of p53 and interferon (IFN) pathways, which enforced cell cycling in quiescent HSPCs, resulting in their apoptotic death. The rapid cell death phenotype was reproducible in in vitro cultured cDKO-hematopoietic stem cells, which were significantly rescued by nucleotide supplementation or after depletion of p53. Collectively, Ssb1 and Ssb2 control crucial aspects of HSPC function, including proliferation and survival in vivo by resolving replicative stress to maintain genomic stability.
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http://dx.doi.org/10.1182/blood-2016-06-725093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418634PMC
May 2017

Histone Acetyltransferase Activity of MOF Is Required for Leukemogenesis.

Cancer Res 2017 04 15;77(7):1753-1762. Epub 2017 Feb 15.

Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.

Chromatin-based mechanisms offer therapeutic targets in acute myeloid leukemia (AML) that are of great current interest. In this study, we conducted an RNAi-based screen to identify druggable chromatin regulator-based targets in leukemias marked by oncogenic rearrangements of the gene. In this manner, we discovered the H4K16 histone acetyltransferase (HAT) MOF to be important for leukemia cell growth. Conditional deletion of in a mouse model of -driven leukemogenesis reduced tumor burden and prolonged host survival. RNA sequencing showed an expected downregulation of genes within DNA damage repair pathways that are controlled by MOF, as correlated with a significant increase in yH2AX nuclear foci in -deficient tumor cells. In parallel, loss also impaired global H4K16 acetylation in the tumor cell genome. Rescue experiments with catalytically inactive mutants of MOF showed that its enzymatic activity was required to maintain cancer pathogenicity. In support of the role of MOF in sustaining H4K16 acetylation, a small-molecule inhibitor of the HAT component MYST blocked the growth of both murine and human leukemia cell lines. Furthermore, inactivation suppressed leukemia development in an -driven AML model. Taken together, our results establish that the HAT activity of MOF is required to sustain leukemia and may be important for multiple AML subtypes. Blocking this activity is sufficient to stimulate DNA damage, offering a rationale to pursue MOF inhibitors as a targeted approach to treat -rearranged leukemias. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-2374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501293PMC
April 2017