Publications by authors named "Veronica Rendo"

11 Publications

  • Page 1 of 1

TIRR inhibits the 53BP1-p53 complex to alter cell-fate programs.

Mol Cell 2021 Jun 6;81(12):2583-2595.e6. Epub 2021 May 6.

Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address:

53BP1 influences genome stability via two independent mechanisms: (1) regulating DNA double-strand break (DSB) repair and (2) enhancing p53 activity. We discovered a protein, Tudor-interacting repair regulator (TIRR), that associates with the 53BP1 Tudor domain and prevents its recruitment to DSBs. Here, we elucidate how TIRR affects 53BP1 function beyond its recruitment to DSBs and biochemically links the two distinct roles of 53BP1. Loss of TIRR causes an aberrant increase in the gene transactivation function of p53, affecting several p53-mediated cell-fate programs. TIRR inhibits the complex formation between the Tudor domain of 53BP1 and a dimethylated form of p53 (K382me2) that is poised for transcriptional activation of its target genes. TIRR mRNA expression levels negatively correlate with the expression of key p53 target genes in breast and prostate cancers. Further, TIRR loss is selectively not tolerated in p53-proficient tumors. Therefore, we establish that TIRR is an important inhibitor of the 53BP1-p53 complex.
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http://dx.doi.org/10.1016/j.molcel.2021.03.039DOI Listing
June 2021

Women in cancer research and oncology.

Cancer Cell 2021 Mar;39(3):285-287

March 8 is International Women's Day. Women, particularly women of color, are still underrepresented in science and medical careers and face severe health disparities. To commemorate this day, we asked female cancer researchers and oncologists to talk about their work experiences and their efforts to improve equity, representation, and leadership.
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http://dx.doi.org/10.1016/j.ccell.2021.02.008DOI Listing
March 2021

Defining eligible patients for allele-selective chemotherapies targeting NAT2 in colorectal cancer.

Sci Rep 2020 12 31;10(1):22436. Epub 2020 Dec 31.

Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 85, Uppsala, Sweden.

Therapies targeting somatic bystander genetic events represent a new avenue for cancer treatment. We recently identified a subset of colorectal cancer (CRC) patients who are heterozygous for a wild-type and a low activity allele (NAT2*6) but lack the wild-type allele in their tumors due to loss of heterozygosity (LOH) at 8p22. These tumors were sensitive to treatment with a cytotoxic substrate of NAT2 (6-(4-aminophenyl)-N-(3,4,5-trimethoxyphenyl)pyrazin-2-amine, APA), and pointed to NAT2 loss being a therapeutically exploitable vulnerability of CRC tumors. To better estimate the total number of treatable CRC patients, we here determined whether tumor cells retaining also other NAT2 low activity variants after LOH respond to APA treatment. The prevalent low activity alleles NAT2*5 and NAT2*14, but not NAT2*7, were found to be low metabolizers with high sensitivity to APA. By analysis of two different CRC patient cohorts, we detected heterozygosity for NAT2 alleles targetable by APA, along with allelic imbalances pointing to LOH, in ~ 24% of tumors. Finally, to haplotype the NAT2 locus in tumor and patient-matched normal samples in a clinical setting, we develop and demonstrate a long-read sequencing based assay. In total, > 79.000 CRC patients per year fulfil genetic criteria for high sensitivity to a NAT2 LOH therapy and their eligibility can be assessed by clinical sequencing.
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http://dx.doi.org/10.1038/s41598-020-80288-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775439PMC
December 2020

Adding to the CASeload: unwarranted p53 signaling induced by Cas9.

Mol Cell Oncol 2020 14;7(5):1789419. Epub 2020 Jul 14.

Department of Human Molecular Genetics & Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

We investigated the genetic and transcriptional changes associated with Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) associated protein 9 (Cas9) expression in human cancer cell lines. For a subset of cell lines with a wild-type tumor protein TP53 (best known as p53), we detected p53 pathway activation, DNA damage accumulation and emerging p53-inactivating mutations following Cas9 introduction. We discuss the potential implications of our findings in basic and translational research.
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http://dx.doi.org/10.1080/23723556.2020.1789419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469564PMC
July 2020

Targeting tumor vulnerabilities associated with loss of heterozygosity.

Mol Cell Oncol 2020 13;7(4):1759390. Epub 2020 May 13.

Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

We show that N-acetyltransferase 2 () loss of heterozygosity can be targeted in >4% of colorectal cancers with the use of a small molecule. We identify and describe the effect of a compound that impairs the growth of colorectal tumors with slow NAT2 activity by half when compared to wild-type.
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http://dx.doi.org/10.1080/23723556.2020.1759390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469497PMC
May 2020

Author Correction: Cas9 activates the p53 pathway and selects for p53-inactivating mutations.

Nat Genet 2020 Jul;52(7):748-749

Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41588-020-0663-9DOI Listing
July 2020

Unexpected Acetylation of Endogenous Aliphatic Amines by Arylamine N-Acetyltransferase NAT2.

Angew Chem Int Ed Engl 2020 08 8;59(34):14342-14346. Epub 2020 Jul 8.

Department of Medicinal Chemistry, Science for Life Laboratory, Uppsala University, Box 574, 75123, Uppsala, Sweden.

N-Acetyltransferases play critical roles in the deactivation and clearance of xenobiotics, including clinical drugs. NAT2 has been classified as an arylamine N-acetyltransferase that mainly converts aromatic amines, hydroxylamines, and hydrazines. Herein, we demonstrate that the human arylamine N-acetyltransferase NAT2 also acetylates aliphatic endogenous amines. Metabolomic analysis and chemical synthesis revealed increased intracellular concentrations of mono- and diacetylated spermidine in human cell lines expressing the rapid compared to the slow acetylator NAT2 phenotype. The regioselective N -acetylation of monoacetylated spermidine by NAT2 answers the long-standing question of the source of diacetylspermidine. We also identified selective acetylation of structurally diverse alkylamine-containing drugs by NAT2, which may contribute to variations in patient responses. The results demonstrate a previously unknown functionality and potential regulatory role for NAT2, and we suggest that this enzyme should be considered for re-classification.
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http://dx.doi.org/10.1002/anie.202005915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497018PMC
August 2020

Cas9 activates the p53 pathway and selects for p53-inactivating mutations.

Nat Genet 2020 07 18;52(7):662-668. Epub 2020 May 18.

Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Cas9 is commonly introduced into cell lines to enable CRISPR-Cas9-mediated genome editing. Here, we studied the genetic and transcriptional consequences of Cas9 expression itself. Gene expression profiling of 165 pairs of human cancer cell lines and their Cas9-expressing derivatives revealed upregulation of the p53 pathway upon introduction of Cas9, specifically in wild-type TP53 (TP53-WT) cell lines. This was confirmed at the messenger RNA and protein levels. Moreover, elevated levels of DNA repair were observed in Cas9-expressing cell lines. Genetic characterization of 42 cell line pairs showed that introduction of Cas9 can lead to the emergence and expansion of p53-inactivating mutations. This was confirmed by competition experiments in isogenic TP53-WT and TP53-null (TP53) cell lines. Lastly, Cas9 was less active in TP53-WT than in TP53-mutant cell lines, and Cas9-induced p53 pathway activation affected cellular sensitivity to both genetic and chemical perturbations. These findings may have broad implications for the proper use of CRISPR-Cas9-mediated genome editing.
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http://dx.doi.org/10.1038/s41588-020-0623-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343612PMC
July 2020

Exploiting loss of heterozygosity for allele-selective colorectal cancer chemotherapy.

Nat Commun 2020 03 11;11(1):1308. Epub 2020 Mar 11.

Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, SE-75185, Uppsala, Sweden.

Cancer chemotherapy targeting frequent loss of heterozygosity events is an attractive concept, since tumor cells may lack enzymatic activities present in normal constitutional cells. To find exploitable targets, we map prevalent genetic polymorphisms to protein structures and identify 45 nsSNVs (non-synonymous small nucleotide variations) near the catalytic sites of 17 enzymes frequently lost in cancer. For proof of concept, we select the gastrointestinal drug metabolic enzyme NAT2 at 8p22, which is frequently lost in colorectal cancers and has a common variant with 10-fold reduced activity. Small molecule screening results in a cytotoxic kinase inhibitor that impairs growth of cells with slow NAT2 and decreases the growth of tumors with slow NAT2 by half as compared to those with wild-type NAT2. Most of the patient-derived CRC cells expressing slow NAT2 also show sensitivity to 6-(4-aminophenyl)-N-(3,4,5-trimethoxyphenyl)pyrazin-2-amine (APA) treatment. These findings indicate that the therapeutic index of anti-cancer drugs can be altered by bystander mutations affecting drug metabolic genes.
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http://dx.doi.org/10.1038/s41467-020-15111-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066191PMC
March 2020

Somatic c.4467delA mutations in colorectal cancers control histone methylation and tumor growth.

Oncotarget 2017 Nov 9;8(58):98646-98659. Epub 2017 Oct 9.

Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

The chromatin modifier is inactivated by mutation in several forms of cancer and is a putative tumor suppressor gene. Frameshift mutations in the C-terminal region of , affecting (A)8 or (A)9 repeats within exon 8, are found in one third of colorectal cancers with microsatellite instability, but the contribution of these mutations to colorectal tumorigenesis is unknown. To model somatic mutations in microsatellite unstable tumors, we devised a general approach to perform genome editing while stabilizing the mutated nucleotide repeat. We then engineered isogenic cell systems where the c.4467delA mutation in human HCT116 colorectal cancer cells was corrected to wild-type by genome editing. Restored increased global histone 3 lysine 9 dimethylation and reduced migration, anchorage-independent growth and tumor growth . Gene set enrichment analysis revealed regulation of several hallmark cancer pathways, particularly of epithelial-to-mesenchymal transition (EMT), with VIM being the most significantly regulated gene. These observations provide direct evidence that c.4467delA is a driver mutation in colorectal cancer and confirms as a cancer gene, pointing to regulation of EMT as a central aspect of its tumor suppressive action.
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http://dx.doi.org/10.18632/oncotarget.21713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716757PMC
November 2017

Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer.

Cancer Res 2017 04 20;77(7):1730-1740. Epub 2017 Jan 20.

Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Sweden.

The contribution of somatic mutations to metastasis of colorectal cancers is currently unknown. To find mutations involved in the colorectal cancer metastatic process, we performed deep mutational analysis of 676 genes in 107 stages II to IV primary colorectal cancer, of which half had metastasized. The mutation prevalence in the ephrin (EPH) family of tyrosine kinase receptors was 10-fold higher in primary tumors of metastatic colorectal than in nonmetastatic cases and preferentially occurred in stage III and IV tumors. Mutational analyses confirmed expression of mutant EPH receptors. To enable functional studies of EPHB1 mutations, we demonstrated that DLD-1 colorectal cancer cells expressing EPHB1 form aggregates upon coculture with ephrin B1 expressing cells. When mutations in the fibronectin type III and kinase domains of EPHB1 were compared with wild-type EPHB1 in DLD-1 colorectal cancer cells, they decreased ephrin B1-induced compartmentalization. These observations provide a mechanistic link between EPHB receptor mutations and metastasis in colorectal cancer. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-1921DOI Listing
April 2017