A role for human homologous recombination factors in suppressing microhomology-mediated end joining.Report as inadecuate




A role for human homologous recombination factors in suppressing microhomology-mediated end joining. - Download this document for free, or read online. Document in PDF available to download.

Reference: Ahrabi, S, Sarkar, S, Pfister, SX et al., (2016). A role for human homologous recombination factors in suppressing microhomology-mediated end joining. Nucleic acids research, gkw326-gkw326.Citable link to this page:

 

A role for human homologous recombination factors in suppressing microhomology-mediated end joining.

Abstract: 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.

Peer Review status:Peer reviewedPublication status:PublishedVersion:Publisher's version Funder: Medical Research Council   Funder: Cancer Research UK   Funder: Clarendon Fund   Funder: Biotechnology and Biological Sciences Research Council   Notes:Copyright © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Bibliographic Details

Publisher: Oxford University Press

Publisher Website: http://www.oxfordjournals.org/

Journal: Nucleic acids researchsee more from them

Publication Website: http://nar.oxfordjournals.org/

Issue Date: 2016

pages:gkw326-gkw326Identifiers

Urn: uuid:4b1c7c4a-ed79-441d-9373-7720e468dfac

Source identifier: 619663

Eissn: 1362-4962

Doi: https://doi.org/10.1093/nar/gkw326

Issn: 0305-1048 Item Description

Type: Journal article;

Language: eng

Version: Publisher's version Tiny URL: pubs:619663

Relationships





Author: Ahrabi, S - institutionUniversity of Oxford Oxford, MSD, Oncology grantNumberC5255-A15935 fundingCancer Research UK fundingClaren

Source: https://ora.ox.ac.uk/objects/uuid:4b1c7c4a-ed79-441d-9373-7720e468dfac



DOWNLOAD PDF




Related documents