دورية أكاديمية
A role for human homologous recombination factors in suppressing microhomology-mediated end joining.
العنوان: | A role for human homologous recombination factors in suppressing microhomology-mediated end joining. |
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المؤلفون: | Ahrabi S; CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK., Sarkar S; CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK., Pfister SX; CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK., Pirovano G; CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK., Higgins GS; CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK., Porter AC; Gene Targeting Group, Centre for Haematology, Imperial College Faculty of Medicine, London W12 0NN, UK., Humphrey TC; CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK timothy.humphrey@oncology.ox.ac.uk. |
المصدر: | Nucleic acids research [Nucleic Acids Res] 2016 Jul 08; Vol. 44 (12), pp. 5743-57. Date of Electronic Publication: 2016 Apr 29. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE |
أسماء مطبوعة: | Publication: 1992- : Oxford : Oxford University Press Original Publication: London, Information Retrieval ltd. |
مواضيع طبية MeSH: | DNA Breaks, Double-Stranded* , DNA End-Joining Repair* , Recombinational DNA Repair*, BRCA1 Protein/*genetics , BRCA2 Protein/*genetics , DNA/*metabolism , Replication Protein A/*genetics, BRCA1 Protein/antagonists & inhibitors ; BRCA1 Protein/metabolism ; BRCA2 Protein/antagonists & inhibitors ; BRCA2 Protein/metabolism ; Base Sequence ; Biological Assay ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Line, Tumor ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; DNA-Directed DNA Polymerase/genetics ; DNA-Directed DNA Polymerase/metabolism ; Endodeoxyribonucleases ; Epithelial Cells/cytology ; Epithelial Cells/metabolism ; Fibroblasts/cytology ; Fibroblasts/metabolism ; Humans ; MRE11 Homologue Protein ; Mutation ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Osteoblasts/cytology ; Osteoblasts/metabolism ; Poly(ADP-ribose) Polymerases/genetics ; Poly(ADP-ribose) Polymerases/metabolism ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; Replication Protein A/antagonists & inhibitors ; Replication Protein A/metabolism ; Sequence Alignment ; Sequence Homology, Nucleic Acid ; DNA Polymerase theta |
مستخلص: | DNA double-strand breaks (DSBs) are toxic lesions, which if improperly repaired can result in cell death or genomic instability. DSB repair is usually facilitated by the classical non-homologous end joining (C-NHEJ), or homologous recombination (HR) pathways. However, a mutagenic alternative NHEJ pathway, microhomology-mediated end joining (MMEJ), can also be deployed. While MMEJ is suppressed by C-NHEJ, the relationship between HR and MMEJ is less clear. Here, we describe a role for HR genes in suppressing MMEJ in human cells. By monitoring DSB mis-repair using a sensitive HPRT assay, we found that depletion of HR proteins, including BRCA2, BRCA1 or RPA, resulted in a distinct mutational signature associated with significant increases in break-induced mutation frequencies, deletion lengths and the annealing of short regions of microhomology (2-6 bp) across the break-site. This signature was dependent on CtIP, MRE11, POLQ and PARP, and thus indicative of MMEJ. In contrast to CtIP or MRE11, depletion of BRCA1 resulted in increased partial resection and MMEJ, thus revealing a functional distinction between these early acting HR factors. Together these findings indicate that HR factors suppress mutagenic MMEJ following DSB resection. (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.) |
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معلومات مُعتمدة: | MC_PC_12003 United Kingdom MRC_ Medical Research Council; 19590 United Kingdom CRUK_ Cancer Research UK; C5255/A15935 United Kingdom CRUK_ Cancer Research UK; MC_PC_12003 United Kingdom MRC_ Medical Research Council; BB/H003371/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; MC_U142784382 United Kingdom MRC_ Medical Research Council; C34326/A13092 United Kingdom CRUK_ Cancer Research UK; C38302/A12981 United Kingdom CRUK_ Cancer Research UK |
المشرفين على المادة: | 0 (BRCA1 Protein) 0 (BRCA1 protein, human) 0 (BRCA2 Protein) 0 (BRCA2 protein, human) 0 (Carrier Proteins) 0 (DNA-Binding Proteins) 0 (MRE11 protein, human) 0 (Nuclear Proteins) 0 (RNA, Small Interfering) 0 (RPA1 protein, human) 0 (Replication Protein A) 9007-49-2 (DNA) EC 2.4.2.30 (Poly(ADP-ribose) Polymerases) EC 2.7.7.7 (DNA-Directed DNA Polymerase) EC 3.1.- (Endodeoxyribonucleases) EC 3.1.- (MRE11 Homologue Protein) EC 3.1.- (RBBP8 protein, human) |
تواريخ الأحداث: | Date Created: 20160501 Date Completed: 20170605 Latest Revision: 20240210 |
رمز التحديث: | 20240210 |
مُعرف محوري في PubMed: | PMC4937322 |
DOI: | 10.1093/nar/gkw326 |
PMID: | 27131361 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1362-4962 |
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DOI: | 10.1093/nar/gkw326 |