Publications by authors named "Jan M van Deursen"

119 Publications

GAS7 Deficiency Promotes Metastasis in MYCN-driven Neuroblastoma.

Cancer Res 2021 Feb 18. Epub 2021 Feb 18.

Department of Biochemistry and Molecular Biology, Mayo Clinic

One of the greatest barriers to curative treatment of neuroblastoma (NB) is its frequent metastatic outgrowth prior to diagnosis, especially in cases driven by amplification of the MYCN oncogene. However, only a limited number of regulatory proteins that contribute to this complex MYCN-mediated process have been elucidated. Here we show that the growth arrest-specific 7 (GAS7) gene, located at chromosome band 17p13.1, is preferentially deleted in high-risk MYCN-driven NB. GAS7 expression was also suppressed in MYCN-amplified NB lacking 17p deletion. GAS7 deficiency led to accelerated metastasis in both zebrafish and mammalian models of NB with overexpression or amplification of MYCN. Analysis of expression profiles and the ultrastructure of zebrafish NB tumors with MYCN overexpression identified that GAS7 deficiency led to (i) downregulation of genes involved in cell-cell interaction, (ii) loss of contact among tumor cells as critical determinants of accelerated metastasis, and (iii) increased levels of MYCN protein. These results provide the first genetic evidence that GAS7 depletion is a critical early step in the cascade of events culminating in NB metastasis in the context of MYCN overexpression.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1890DOI Listing
February 2021

CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD and NMN levels.

Nat Metab 2020 11 16;2(11):1284-1304. Epub 2020 Nov 16.

Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.

Decreased NAD levels have been shown to contribute to metabolic dysfunction during aging. NAD decline can be partially prevented by knockout of the enzyme CD38. However, it is not known how CD38 is regulated during aging, and how its ecto-enzymatic activity impacts NAD homeostasis. Here we show that an increase in CD38 in white adipose tissue (WAT) and the liver during aging is mediated by accumulation of CD38 immune cells. Inflammation increases CD38 and decreases NAD. In addition, senescent cells and their secreted signals promote accumulation of CD38 cells in WAT, and ablation of senescent cells or their secretory phenotype decreases CD38, partially reversing NAD decline. Finally, blocking the ecto-enzymatic activity of CD38 can increase NAD through a nicotinamide mononucleotide (NMN)-dependent process. Our findings demonstrate that senescence-induced inflammation promotes accumulation of CD38 in immune cells that, through its ecto-enzymatic activity, decreases levels of NMN and NAD.
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http://dx.doi.org/10.1038/s42255-020-00298-zDOI Listing
November 2020

E2F7 Is a Potent Inhibitor of Liver Tumor Growth in Adult Mice.

Hepatology 2021 Jan;73(1):303-317

Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.

Background And Aims: Up-regulation of the E2F-dependent transcriptional network has been identified in nearly every human malignancy and is an important driver of tumorigenesis. Two members of the E2F family, E2F7 and E2F8, are potent repressors of E2F-dependent transcription. They are atypical in that they do not bind to dimerization partner proteins and are not controlled by retinoblastoma protein. The physiological relevance of E2F7 and E2F8 remains incompletely understood, largely because tools to manipulate their activity in vivo have been lacking.

Approach And Results: Here, we generated transgenic mice with doxycycline-controlled transcriptional activation of E2f7 and E2f8 and induced their expression during postnatal development, in adulthood, and in the context of cancer. Systemic induction of E2f7 and, to lesser extent, E2f8 transgenes in juvenile mice impaired cell proliferation, caused replication stress, DNA damage, and apoptosis, and inhibited animal growth. In adult mice, however, E2F7 and E2F8 induction was well tolerated, yet profoundly interfered with DNA replication, DNA integrity, and cell proliferation in diethylnitrosamine-induced liver tumors.

Conclusion: Collectively, our findings demonstrate that atypical E2Fs can override cell-cycle entry and progression governed by other E2F family members and suggest that this property can be exploited to inhibit proliferation of neoplastic hepatocytes when growth and development have subsided during adulthood.
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http://dx.doi.org/10.1002/hep.31259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898887PMC
January 2021

Requirement of the Cep57-Cep63 Interaction for Proper Cep152 Recruitment and Centriole Duplication.

Mol Cell Biol 2020 04 28;40(10). Epub 2020 Apr 28.

Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

Cep57 has been characterized as a component of a pericentriolar complex containing Cep63 and Cep152. Interestingly, Cep63 and Cep152 self-assemble into a pericentriolar cylindrical architecture, and this event is critical for the orderly recruitment of Plk4, a key regulator of centriole duplication. However, the way in which Cep57 interacts with the Cep63-Cep152 complex and contributes to the structure and function of Cep63-Cep152 self-assembly remains unknown. We demonstrate that Cep57 interacts with Cep63 through N-terminal motifs and associates with Cep152 via Cep63. Three-dimensional structured illumination microscopy (3D-SIM) analyses suggested that the Cep57-Cep63-Cep152 complex is concentrically arranged around a centriole in a Cep57-in and Cep152-out manner. Cep57 mutant cells defective in Cep63 binding exhibited improper Cep63 and Cep152 localization and impaired Sas6 recruitment for procentriole assembly, proving the significance of the Cep57-Cep63 interaction. Intriguingly, Cep63 fused to a microtubule (MT)-binding domain of Cep57 functioned in concert with Cep152 to assemble around stabilized MTs Thus, Cep57 plays a key role in architecting the Cep63-Cep152 assembly around centriolar MTs and promoting centriole biogenesis. This study may offer a platform to investigate how the organization and function of the pericentriolar architecture are altered by disease-associated mutations found in the Cep57-Cep63-Cep152 complex.
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http://dx.doi.org/10.1128/MCB.00535-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189096PMC
April 2020

Therapy-Induced Senescence Drives Bone Loss.

Cancer Res 2020 03 13;80(5):1171-1182. Epub 2020 Jan 13.

Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri.

Chemotherapy is important for cancer treatment, however, toxicities limit its use. While great strides have been made to ameliorate the acute toxicities induced by chemotherapy, long-term comorbidities including bone loss remain a significant problem. Chemotherapy-driven estrogen loss is postulated to drive bone loss, but significant data suggests the existence of an estrogen-independent mechanism of bone loss. Using clinically relevant mouse models, we showed that senescence and its senescence-associated secretory phenotype (SASP) contribute to chemotherapy-induced bone loss that can be rescued by depleting senescent cells. Chemotherapy-induced SASP could be limited by targeting the p38MAPK-MK2 pathway, which resulted in preservation of bone integrity in chemotherapy-treated mice. These results transform our understanding of chemotherapy-induced bone loss by identifying senescent cells as major drivers of bone loss and the p38MAPK-MK2 axis as a putative therapeutic target that can preserve bone and improve a cancer survivor's quality of life. SIGNIFICANCE: Senescence drives chemotherapy-induced bone loss that is rescued by p38MAPK or MK2 inhibitors. These findings may lead to treatments for therapy-induced bone loss, significantly increasing quality of life for cancer survivors.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056549PMC
March 2020

BubR1 allelic effects drive phenotypic heterogeneity in mosaic-variegated aneuploidy progeria syndrome.

J Clin Invest 2020 01;130(1):171-188

Departments of Biochemistry and Molecular Biology.

Mosaic-variegated aneuploidy (MVA) syndrome is a rare childhood disorder characterized by biallelic BUBR1, CEP57, or TRIP13 aberrations; increased chromosome missegregation; and a broad spectrum of clinical features, including various cancers, congenital defects, and progeroid pathologies. To investigate the mechanisms underlying this disorder and its phenotypic heterogeneity, we mimicked the BUBR1L1012P mutation in mice (BubR1L1002P) and combined it with 2 other MVA variants, BUBR1X753 and BUBR1H, generating a truncated protein and low amounts of wild-type protein, respectively. Whereas BubR1X753/L1002P and BubR1H/X753 mice died prematurely, BubR1H/L1002P mice were viable and exhibited many MVA features, including cancer predisposition and various progeroid phenotypes, such as short lifespan, dwarfism, lipodystrophy, sarcopenia, and low cardiac stress tolerance. Strikingly, although these mice had a reduction in total BUBR1 and spectrum of MVA phenotypes similar to that of BubR1H/H mice, several progeroid pathologies were attenuated in severity, which in skeletal muscle coincided with reduced senescence-associated secretory phenotype complexity. Additionally, mice carrying monoallelic BubR1 mutations were prone to select MVA-related pathologies later in life, with predisposition to sarcopenia correlating with mTORC1 hyperactivity. Together, these data demonstrate that BUBR1 allelic effects beyond protein level and aneuploidy contribute to disease heterogeneity in both MVA patients and heterozygous carriers of MVA mutations.
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http://dx.doi.org/10.1172/JCI126863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934189PMC
January 2020

Crystallizing BubR1's kinase activity.

Cell Res 2019 08;29(8):605-606

Departments of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, 55905, USA.

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http://dx.doi.org/10.1038/s41422-019-0199-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796944PMC
August 2019

Pak2 kinase promotes cellular senescence and organismal aging.

Proc Natl Acad Sci U S A 2019 07 17;116(27):13311-13319. Epub 2019 Jun 17.

Institute for Cancer Genetics, Columbia University Irving Medical Center, New York, NY 10032;

Cellular senescence defines an irreversible cell growth arrest state linked to loss of tissue function and aging in mammals. This transition from proliferation to senescence is typically characterized by increased expression of the cell-cycle inhibitor p16 and formation of senescence-associated heterochromatin foci (SAHF). SAHF formation depends on HIRA-mediated nucleosome assembly of histone H3.3, which is regulated by the serine/threonine protein kinase Pak2. However, it is unknown if Pak2 contributes to cellular senescence. Here, we show that depletion of Pak2 delayed oncogene-induced senescence in IMR90 human fibroblasts and oxidative stress-induced senescence of mouse embryonic fibroblasts (MEFs), whereas overexpression of Pak2 accelerated senescence of IMR90 cells. Importantly, depletion of Pak2 in BubR1 progeroid mice attenuated the onset of aging-associated phenotypes and extended life span. Pak2 is required for expression of genes involved in cellular senescence and regulated the deposition of newly synthesized H3.3 onto chromatin in senescent cells. Together, our results demonstrate that Pak2 is an important regulator of cellular senescence and organismal aging, in part through the regulation of gene expression and H3.3 nucleosome assembly.
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http://dx.doi.org/10.1073/pnas.1903847116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613284PMC
July 2019

Senolytic therapies for healthy longevity.

Science 2019 05;364(6441):636-637

Departments of Biochemistry and Molecular Biology, and Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN 55905, USA.

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http://dx.doi.org/10.1126/science.aaw1299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816502PMC
May 2019

Senescent cells in the development of cardiometabolic disease.

Curr Opin Lipidol 2019 06;30(3):177-185

Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Purpose Of Review: Senescent cells have recently been identified as key players in the development of metabolic dysfunction. In this review, we will highlight recent developments in this field and discuss the concept of targeting these cells to prevent or treat cardiometabolic diseases.

Recent Findings: Evidence is accumulating that cellular senescence contributes to adipose tissue dysfunction, presumably through induction of low-grade inflammation and inhibition of adipogenic differentiation leading to insulin resistance and dyslipidaemia. Senescent cells modulate their surroundings through their bioactive secretome and only a relatively small number of senescent cells is sufficient to cause persistent physical dysfunction even in young mice. Proof-of-principle studies showed that selective elimination of senescent cells can prevent or delay the development of cardiometabolic diseases in mice.

Summary: The metabolic consequences of senescent cell accumulation in various tissues are now unravelling and point to new therapeutic opportunities for the treatment of cardiometabolic diseases.
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http://dx.doi.org/10.1097/MOL.0000000000000602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530963PMC
June 2019

Ccne1 Overexpression Causes Chromosome Instability in Liver Cells and Liver Tumor Development in Mice.

Gastroenterology 2019 07 13;157(1):210-226.e12. Epub 2019 Mar 13.

Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota; Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota; Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address:

Background & Aims: The CCNE1 locus, which encodes cyclin E1, is amplified in many types of cancer cells and is activated in hepatocellular carcinomas (HCCs) from patients infected with hepatitis B virus or adeno-associated virus type 2, due to integration of the virus nearby. We investigated cell-cycle and oncogenic effects of cyclin E1 overexpression in tissues of mice.

Methods: We generated mice with doxycycline-inducible expression of Ccne1 (Ccne1 mice) and activated overexpression of cyclin E1 from age 3 weeks onward. At 14 months of age, livers were collected from mice that overexpress cyclin E1 and nontransgenic mice (controls) and analyzed for tumor burden and by histology. Mouse embryonic fibroblasts (MEFs) and hepatocytes from Ccne1 and control mice were analyzed to determine the extent to which cyclin E1 overexpression perturbs S-phase entry, DNA replication, and numbers and structures of chromosomes. Tissues from 4-month-old Ccne1 and control mice (at that age were free of tumors) were analyzed for chromosome alterations, to investigate the mechanisms by which cyclin E1 predisposes hepatocytes to transformation.

Results: Ccne1 mice developed more hepatocellular adenomas and HCCs than control mice. Tumors developed only in livers of Ccne1 mice, despite high levels of cyclin E1 in other tissues. Ccne1 MEFs had defects that promoted chromosome missegregation and aneuploidy, including incomplete replication of DNA, centrosome amplification, and formation of nonperpendicular mitotic spindles. Whereas Ccne1 mice accumulated near-diploid aneuploid cells in multiple tissues and organs, polyploidization was observed only in hepatocytes, with losses and gains of whole chromosomes, DNA damage, and oxidative stress.

Conclusions: Livers, but not other tissues of mice with inducible overexpression of cyclin E1, develop tumors. More hepatocytes from the cyclin E1-overexpressing mice were polyploid than from control mice, and had losses or gains of whole chromosomes, DNA damage, and oxidative stress; all of these have been observed in human HCC cells. The increased risk of HCC in patients with hepatitis B virus or adeno-associated virus type 2 infection might involve activation of cyclin E1 and its effects on chromosomes and genomes of liver cells.
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http://dx.doi.org/10.1053/j.gastro.2019.03.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800187PMC
July 2019

Nearly complete deletion of BubR1 causes microcephaly through shortened mitosis and massive cell death.

Hum Mol Genet 2019 06;28(11):1822-1836

Shriners Hospitals Pediatric Research Center, Department of Anatomy and Cell Biology, Lewis Katz School of Medicine Temple University, Philadelphia, PA, USA.

BUB-related 1 (BubR1) encoded by Budding Uninhibited by Benzimidazole 1B (BUB1B) is a crucial mitotic checkpoint protein ensuring proper segregation of chromosomes during mitosis. Mutations of BUB1B are responsible for mosaic variegated aneuploidy (MVA), a human congenital disorder characterized by extensive abnormalities in chromosome number. Although microcephaly is a prominent feature of MVA carrying the BUB1B mutation, how BubR1 deficiency disturbs neural progenitor proliferation and neuronal output and leads to microcephaly is unknown. Here we show that conditional loss of BubR1 in mouse cerebral cortex recapitulates microcephaly. BubR1-deficient cortex includes a strikingly reduced number of late-born, but not of early-born, neurons, although BubR1 expression is substantially reduced from an early stage. Importantly, absence of BubR1 decreases the proportion of neural progenitors in mitosis, specifically in metaphase, suggesting shortened mitosis owing to premature chromosome segregation. In the BubR1 mutant, massive apoptotic cell death, which is likely due to the compromised genomic integrity that results from aberrant mitosis, depletes progenitors and neurons during neurogenesis. There is no apparent alteration in centrosome number, spindle formation or primary cilia, suggesting that the major effect of BubR1 deficiency on neural progenitors is to impair the mitotic checkpoint. This finding highlights the importance of the mitotic checkpoint in the pathogenesis of microcephaly. Furthermore, the ependymal cell layer does not form in the conditional knockout, revealing an unrecognized role of BubR1 in assuring the integrity of the ventricular system, which may account for the presence of hydrocephalus in some patients.
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http://dx.doi.org/10.1093/hmg/ddz022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522074PMC
June 2019

sFRP3 inhibition improves age-related cellular changes in BubR1 progeroid mice.

Aging Cell 2019 04 4;18(2):e12899. Epub 2019 Jan 4.

Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota.

Wnt signaling is a well-known molecular pathway in age-related pathogenesis and therapy of disease. While prior studies have mainly focused on Wnt ligands or Wnt activators, the in vivo functions of naturally secreted Wnt inhibitors are not clear, especially in brain aging. Using BubR1 mice as a novel mouse model of accelerated aging, we report that genetic inhibition of sFRP3 restores the reduced body and brain size observed in BubR1 mice. Furthermore, sFRP3 inhibition ameliorates hypomyelination in the corpus callosum and rescues neural progenitor proliferation in the hippocampal dentate gyrus of BubR1 mice. Taken together, our study identifies sFRP3 as a new molecular factor that cooperates with BubR1 function to regulate brain development, myelination, and hippocampal neurogenesis.
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http://dx.doi.org/10.1111/acel.12899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413750PMC
April 2019

Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline.

Nature 2018 10 19;562(7728):578-582. Epub 2018 Sep 19.

Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.

Cellular senescence, which is characterized by an irreversible cell-cycle arrest accompanied by a distinctive secretory phenotype, can be induced through various intracellular and extracellular factors. Senescent cells that express the cell cycle inhibitory protein p16 have been found to actively drive naturally occurring age-related tissue deterioration and contribute to several diseases associated with ageing, including atherosclerosis and osteoarthritis. Various markers of senescence have been observed in patients with neurodegenerative diseases; however, a role for senescent cells in the aetiology of these pathologies is unknown. Here we show a causal link between the accumulation of senescent cells and cognition-associated neuronal loss. We found that the MAPTPS19 mouse model of tau-dependent neurodegenerative disease accumulates p16-positive senescent astrocytes and microglia. Clearance of these cells as they arise using INK-ATTAC transgenic mice prevents gliosis, hyperphosphorylation of both soluble and insoluble tau leading to neurofibrillary tangle deposition, and degeneration of cortical and hippocampal neurons, thus preserving cognitive function. Pharmacological intervention with a first-generation senolytic modulates tau aggregation. Collectively, these results show that senescent cells have a role in the initiation and progression of tau-mediated disease, and suggest that targeting senescent cells may provide a therapeutic avenue for the treatment of these pathologies.
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http://dx.doi.org/10.1038/s41586-018-0543-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206507PMC
October 2018

Mosaic-variegated aneuploidy syndrome mutation or haploinsufficiency in Cep57 impairs tumor suppression.

J Clin Invest 2018 08 23;128(8):3517-3534. Epub 2018 Jul 23.

Department of Biochemistry and Molecular Biology and.

A homozygous truncating frameshift mutation in CEP57 (CEP57T/T) has been identified in a subset of mosaic-variegated aneuploidy (MVA) patients; however, the physiological roles of the centrosome-associated protein CEP57 that contribute to disease are unknown. To investigate these, we have generated a mouse model mimicking this disease mutation. Cep57T/T mice died within 24 hours after birth with short, curly tails and severely impaired vertebral ossification. Osteoblasts in lumbosacral vertebrae of Cep57T/T mice were deficient for Fgf2, a Cep57 binding partner implicated in diverse biological processes, including bone formation. Furthermore, a broad spectrum of tissues of Cep57T/T mice had severe aneuploidy at birth, consistent with the MVA patient phenotype. Cep57T/T mouse embryonic fibroblasts and patient-derived skin fibroblasts failed to undergo centrosome maturation in G2 phase, causing premature centriole disjunction, centrosome amplification, aberrant spindle formation, and high rates of chromosome missegregation. Mice heterozygous for the truncating frameshift mutation or a Cep57-null allele were overtly indistinguishable from WT mice despite reduced Cep57 protein levels, yet prone to aneuploidization and cancer, with tumors lacking evidence for loss of heterozygosity. This study identifies Cep57 as a haploinsufficient tumor suppressor with biologically diverse roles in centrosome maturation and Fgf2-mediated bone formation.
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http://dx.doi.org/10.1172/JCI120316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063474PMC
August 2018

ZNF506-dependent positive feedback loop regulates H2AX signaling after DNA damage.

Nat Commun 2018 07 16;9(1):2736. Epub 2018 Jul 16.

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA.

Cells respond to cytotoxic DNA double-strand breaks by recruiting repair proteins to the damaged site. Phosphorylation of the histone variant H2AX at S139 and Y142 modulate its interaction with downstream DNA repair proteins and their recruitment to DNA lesions. Here we report ATM-dependent ZNF506 localization to the lesion through MDC1 following DNA damage. ZNF506, in turn, recruits the protein phosphatase EYA, resulting in dephosphorylation of H2AX at Y142, which further facilitates the recruitment of MDC1 and other downstream repair factors. Thus, ZNF506 regulates the early dynamic signaling in the DNA damage response (DDR) pathway and controls progressive downstream signal amplification. Cells lacking ZNF506 or harboring mutations found in cancer patient samples are more sensitive to radiation, offering a potential new therapeutic option for cancers with mutations in this pathway. Taken together, these results demonstrate how the DDR pathway is orchestrated by ZNF506 to maintain genomic integrity.
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http://dx.doi.org/10.1038/s41467-018-05161-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048040PMC
July 2018

Two-Step Senescence-Focused Cancer Therapies.

Trends Cell Biol 2018 09 17;28(9):723-737. Epub 2018 May 17.

Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Department of Pediatric and Adolescent Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Electronic address:

Damaged cells at risk of neoplastic transformation can be neutralized by apoptosis or engagement of the senescence program, which induces permanent cell-cycle arrest and a bioactive secretome that is implicated in tumor immunosurveillance. While from an evolutionary perspective senescence is beneficial in that it protects against malignancies, the accumulation of senescent cells in tissues and organs with aging and at sites of various pathologies is largely detrimental. Because induction of senescence in cancer cells is emerging as a therapeutic concept, it will be important to consider these detrimental effects, including tumor-promoting properties that may drive the formation of secondary tumors or cancer relapse. In this review we discuss the complex relationship between senescence and cancer, and highlight important considerations for therapeutics.
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http://dx.doi.org/10.1016/j.tcb.2018.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102047PMC
September 2018

Senescent cells: a therapeutic target for cardiovascular disease.

J Clin Invest 2018 04 2;128(4):1217-1228. Epub 2018 Apr 2.

Department of Biochemistry and Molecular Biology.

Cellular senescence, a major tumor-suppressive cell fate, has emerged from humble beginnings as an in vitro phenomenon into recognition as a fundamental mechanism of aging. In the process, senescent cells have attracted attention as a therapeutic target for age-related diseases, including cardiovascular disease (CVD), the leading cause of morbidity and mortality in the elderly. Given the aging global population and the inadequacy of current medical management, attenuating the health care burden of CVD would be transformative to clinical practice. Here, we review the evidence that cellular senescence drives CVD in a bimodal fashion by both priming the aged cardiovascular system for disease and driving established disease forward. Hence, the growing field of senotherapy (neutralizing senescent cells for therapeutic benefit) is poised to contribute to both prevention and treatment of CVD.
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http://dx.doi.org/10.1172/JCI95146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873883PMC
April 2018

L3MBTL2 orchestrates ubiquitin signalling by dictating the sequential recruitment of RNF8 and RNF168 after DNA damage.

Nat Cell Biol 2018 04 26;20(4):455-464. Epub 2018 Mar 26.

Department of Oncology, Mayo Clinic, Rochester, MN, USA.

Cells respond to cytotoxic DNA double-strand breaks (DSBs) by recruiting DNA repair proteins to the damaged site. This recruitment is dependent on ubiquitylation of adjacent chromatin areas by E3 ubiquitin ligases such as RNF8 and RNF168, which are recruited sequentially to the DSBs. However, it is unclear what dictates the sequential order and recruits RNF168 to the DNA lesion. Here, we reveal that L3MBTL2 (lethal(3)malignant brain tumour-like protein 2) is the missing link between RNF8 and RNF168. We found that L3MBTL2 is recruited by MDC1 and subsequently ubiquitylated by RNF8. Ubiquitylated L3MBTL2, in turn, facilitates recruitment of RNF168 to the DNA lesion and promotes DNA DSB repair. These results identify L3MBTL2 as a key target of RNF8 following DNA damage and demonstrates how the DNA damage response pathway is orchestrated by ubiquitin signalling.
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http://dx.doi.org/10.1038/s41556-018-0071-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6083879PMC
April 2018

Accumulation of 5-oxoproline in myocardial dysfunction and the protective effects of OPLAH.

Sci Transl Med 2017 Nov;9(415)

Department of Cardiology, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, Netherlands.

In response to heart failure (HF), the heart reacts by repressing adult genes and expressing fetal genes, thereby returning to a more fetal-like gene profile. To identify genes involved in this process, we carried out transcriptional analysis on murine hearts at different stages of development and on hearts from adult mice with HF. Our screen identified , encoding for 5-oxoprolinase, a member of the γ-glutamyl cycle that functions by scavenging 5-oxoproline. OPLAH depletion occurred as a result of cardiac injury, leading to elevated 5-oxoproline and oxidative stress, whereas OPLAH overexpression improved cardiac function after ischemic injury. In HF patients, we observed elevated plasma 5-oxoproline, which was associated with a worse clinical outcome. Understanding and modulating fetal-like genes in the failing heart may lead to potential diagnostic, prognostic, and therapeutic options in HF.
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http://dx.doi.org/10.1126/scitranslmed.aam8574DOI Listing
November 2017

Mps1 kinase-dependent Sgo2 centromere localisation mediates cohesin protection in mouse oocyte meiosis I.

Nat Commun 2017 09 25;8(1):694. Epub 2017 Sep 25.

Sorbonne Universités, UPMC Univ. Paris 06, Institut de Biologie Paris Seine (IBPS), UMR7622, Paris, 75005, France.

A key feature of meiosis is the step-wise removal of cohesin, the protein complex holding sister chromatids together, first from arms in meiosis I and then from the centromere region in meiosis II. Centromeric cohesin is protected by Sgo2 from Separase-mediated cleavage, in order to maintain sister chromatids together until their separation in meiosis II. Failures in step-wise cohesin removal result in aneuploid gametes, preventing the generation of healthy embryos. Here, we report that kinase activities of Bub1 and Mps1 are required for Sgo2 localisation to the centromere region. Mps1 inhibitor-treated oocytes are defective in centromeric cohesin protection, whereas oocytes devoid of Bub1 kinase activity, which cannot phosphorylate H2A at T121, are not perturbed in cohesin protection as long as Mps1 is functional. Mps1 and Bub1 kinase activities localise Sgo2 in meiosis I preferentially to the centromere and pericentromere respectively, indicating that Sgo2 at the centromere is required for protection.In meiosis I centromeric cohesin is protected by Sgo2 from Separase-mediated cleavage ensuring that sister chromatids are kept together until their separation in meiosis II. Here the authors demonstrate that Bub1 and Mps1 kinase activities are required for Sgo2 localisation to the centromere region.
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http://dx.doi.org/10.1038/s41467-017-00774-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612927PMC
September 2017

LMO1 Synergizes with MYCN to Promote Neuroblastoma Initiation and Metastasis.

Cancer Cell 2017 09 31;32(3):310-323.e5. Epub 2017 Aug 31.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

A genome-wide association study identified LMO1, which encodes an LIM-domain-only transcriptional cofactor, as a neuroblastoma susceptibility gene that functions as an oncogene in high-risk neuroblastoma. Here we show that dβh promoter-mediated expression of LMO1 in zebrafish synergizes with MYCN to increase the proliferation of hyperplastic sympathoadrenal precursor cells, leading to a reduced latency and increased penetrance of neuroblastomagenesis. The transgenic expression of LMO1 also promoted hematogenous dissemination and distant metastasis, which was linked to neuroblastoma cell invasion and migration, and elevated expression levels of genes affecting tumor cell-extracellular matrix interaction, including loxl3, itga2b, itga3, and itga5. Our results provide in vivo validation of LMO1 as an important oncogene that promotes neuroblastoma initiation, progression, and widespread metastatic dissemination.
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http://dx.doi.org/10.1016/j.ccell.2017.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605802PMC
September 2017

Senescent cells: an emerging target for diseases of ageing.

Nat Rev Drug Discov 2017 Oct 21;16(10):718-735. Epub 2017 Jul 21.

Departments of Biochemistry and Molecular Biology, Mayo Clinic.

Chronological age represents the single greatest risk factor for human disease. One plausible explanation for this correlation is that mechanisms that drive ageing might also promote age-related diseases. Cellular senescence, which is a permanent state of cell cycle arrest induced by cellular stress, has recently emerged as a fundamental ageing mechanism that also contributes to diseases of late life, including cancer, atherosclerosis and osteoarthritis. Therapeutic strategies that safely interfere with the detrimental effects of cellular senescence, such as the selective elimination of senescent cells (SNCs) or the disruption of the SNC secretome, are gaining significant attention, with several programmes now nearing human clinical studies.
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http://dx.doi.org/10.1038/nrd.2017.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942225PMC
October 2017

Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment.

Nat Med 2017 Jun 24;23(6):775-781. Epub 2017 Apr 24.

Translational Tissue Engineering Center, Wilmer Eye Institute and the Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.

Senescent cells (SnCs) accumulate in many vertebrate tissues with age and contribute to age-related pathologies, presumably through their secretion of factors contributing to the senescence-associated secretory phenotype (SASP). Removal of SnCs delays several pathologies and increases healthy lifespan. Aging and trauma are risk factors for the development of osteoarthritis (OA), a chronic disease characterized by degeneration of articular cartilage leading to pain and physical disability. Senescent chondrocytes are found in cartilage tissue isolated from patients undergoing joint replacement surgery, yet their role in disease pathogenesis is unknown. To test the idea that SnCs might play a causative role in OA, we used the p16-3MR transgenic mouse, which harbors a p16 (Cdkn2a) promoter driving the expression of a fusion protein containing synthetic Renilla luciferase and monomeric red fluorescent protein domains, as well as a truncated form of herpes simplex virus 1 thymidine kinase (HSV-TK). This mouse strain allowed us to selectively follow and remove SnCs after anterior cruciate ligament transection (ACLT). We found that SnCs accumulated in the articular cartilage and synovium after ACLT, and selective elimination of these cells attenuated the development of post-traumatic OA, reduced pain and increased cartilage development. Intra-articular injection of a senolytic molecule that selectively killed SnCs validated these results in transgenic, non-transgenic and aged mice. Selective removal of the SnCs from in vitro cultures of chondrocytes isolated from patients with OA undergoing total knee replacement decreased expression of senescent and inflammatory markers while also increasing expression of cartilage tissue extracellular matrix proteins. Collectively, these findings support the use of SnCs as a therapeutic target for treating degenerative joint disease.
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http://dx.doi.org/10.1038/nm.4324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785239PMC
June 2017

Oncogenic senescence: a multi-functional perspective.

Oncotarget 2017 Apr;8(16):27661-27672

Division of Cancer Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Cellular senescence is defined as an irreversible growth arrest with the acquisition of a distinctive secretome. The growth arrest is a potent anticancer mechanism whereas the secretome facilitates wound healing, tissue repair, and development. The senescence response has also become increasingly recognized as an important contributor to aging and age-related diseases, including cancer. Although oncogenic mutations are capable of inducing a beneficial senescence response that prevents the growth of premalignant cells and promotes cancer immune-surveillance, the secretome of senescent cells also includes factors with pro-tumorigenic properties. On June 23rd and 24th, 2016, the Division of Cancer Biology of the National Cancer Institute sponsored a workshop to discuss the complex role of cellular senescence in tumorigenesis with the goal to define the major challenges and opportunities within this important field of cancer research. Additionally, it was noted how the development of novel tools and technologies are required to accelerate research into a mechanistic understanding of senescent cells in carcinogenesis in order to overcome the current limitations in this exciting, yet ill-defined area.
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http://dx.doi.org/10.18632/oncotarget.15742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432366PMC
April 2017

Age-related decline in BubR1 impairs adult hippocampal neurogenesis.

Aging Cell 2017 06 6;16(3):598-601. Epub 2017 Apr 6.

Department of Neurologic Surgery, Mayo Clinic College of Medicine, Rochester, MN, USA.

Aging causes significant declines in adult hippocampal neurogenesis and leads to cognitive disability. Emerging evidence demonstrates that decline in the mitotic checkpoint kinase BubR1 level occurs with natural aging and induces progeroid features in both mice and children with mosaic variegated aneuploidy syndrome. Whether BubR1 contributes to age-related deficits in hippocampal neurogenesis is yet to be determined. Here we report that BubR1 expression is significantly reduced with natural aging in the mouse brain. Using established progeroid mice expressing low amounts of BubR1, we demonstrate these mice exhibit deficits in neural progenitor proliferation and maturation, leading to reduction in new neuron production. Collectively, our identification of BubR1 as a new and critical factor controlling sequential steps across neurogenesis raises the possibility that BubR1 may be a key mediator regulating aging-related hippocampal pathology. Targeting BubR1 may represent a novel therapeutic strategy for age-related cognitive deficits.
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http://dx.doi.org/10.1111/acel.12594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418205PMC
June 2017

Caloric Restriction and Rapamycin Differentially Alter Energy Metabolism in Yeast.

J Gerontol A Biol Sci Med Sci 2017 Dec;73(1):29-38

Institute of Animal Molecular Biotechnology, Korea University, Seoul, Republic of Korea.

Rapamycin (RM), a drug that inhibits the mechanistic target of rapamycin (mTOR) pathway and responds to nutrient availability, seemingly mimics the effects of caloric restriction (CR) on healthy life span. However, the extent of the mechanistic overlap between RM and CR remains incompletely understood. Here, we compared the impact of CR and RM on cellular metabolic status. Both regimens maintained intracellular ATP through the chronological aging process and showed enhanced mitochondrial capacity. Comparative transcriptome analysis showed that CR had a stronger impact on global gene expression than RM. We observed a like impact on the metabolome and identified distinct metabolites affected by CR and RM. CR severely reduced the level of energy storage molecules including glycogen and lipid droplets, whereas RM did not. RM boosted the production of enzymes responsible for the breakdown of glycogen and lipid droplets. Collectively, these results provide insights into the distinct energy metabolism mechanisms induced by CR and RM, suggesting that these two anti-aging regimens might extend life span through distinctive pathways.
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http://dx.doi.org/10.1093/gerona/glx024DOI Listing
December 2017

Spartan deficiency causes accumulation of Topoisomerase 1 cleavage complexes and tumorigenesis.

Nucleic Acids Res 2017 05;45(8):4564-4576

Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.

Germline mutations in SPRTN cause Ruijs-Aalfs syndrome (RJALS), a disorder characterized by genome instability, progeria and early onset hepatocellular carcinoma. Spartan, the protein encoded by SPRTN, is a nuclear metalloprotease that is involved in the repair of DNA-protein crosslinks (DPCs). Although Sprtn hypomorphic mice recapitulate key progeroid phenotypes of RJALS, whether this model expressing low amounts of Spartan is prone to DPC repair defects and spontaneous tumors is unknown. Here, we showed that the livers of Sprtn hypomorphic mice accumulate DPCs containing Topoisomerase 1 covalently linked to DNA. Furthermore, these mice exhibited DNA damage, aneuploidy and spontaneous tumorigenesis in the liver. Collectively, these findings provide evidence that partial loss of Spartan impairs DPC repair and tumor suppression.
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http://dx.doi.org/10.1093/nar/gkx107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5416836PMC
May 2017

Singling Out Chromosome Gains in Tumor Evolution.

Cancer Cell 2017 02;31(2):165-166

Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Department of Pediatric and Adolescent Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Electronic address:

In this issue of Cancer Cell, Sheltzer et al. shed new light on Theodor Boveri's century-old hypothesis by demonstrating that aneuploidy characterized by single-chromosome gains acts to suppress tumorigenesis and that aneuploidy itself is a nidus for genomic instability.
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http://dx.doi.org/10.1016/j.ccell.2017.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446207PMC
February 2017