Cargando…

PARP2 controls double-strand break repair pathway choice by limiting 53BP1 accumulation at DNA damage sites and promoting end-resection

Double strand breaks (DSBs) are one of the most toxic lesions to cells. DSB repair by the canonical non-homologous end-joining (C-EJ) pathway involves minor, if any, processing of the broken DNA-ends, whereas the initiation of DNA resection channels the broken-ends toward DNA repair pathways using v...

Descripción completa

Detalles Bibliográficos
Autores principales: Fouquin, Alexis, Guirouilh-Barbat, Josée, Lopez, Bernard, Hall, Janet, Amor-Guéret, Mounira, Pennaneach, Vincent
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716083/
https://www.ncbi.nlm.nih.gov/pubmed/29036662
http://dx.doi.org/10.1093/nar/gkx881
_version_ 1783283874970730496
author Fouquin, Alexis
Guirouilh-Barbat, Josée
Lopez, Bernard
Hall, Janet
Amor-Guéret, Mounira
Pennaneach, Vincent
author_facet Fouquin, Alexis
Guirouilh-Barbat, Josée
Lopez, Bernard
Hall, Janet
Amor-Guéret, Mounira
Pennaneach, Vincent
author_sort Fouquin, Alexis
collection PubMed
description Double strand breaks (DSBs) are one of the most toxic lesions to cells. DSB repair by the canonical non-homologous end-joining (C-EJ) pathway involves minor, if any, processing of the broken DNA-ends, whereas the initiation of DNA resection channels the broken-ends toward DNA repair pathways using various lengths of homology. Mechanisms that control the resection initiation are thus central to the regulation to the choice of DSB repair pathway. Therefore, understanding the mechanisms which regulate the initiation of DNA end-resection is of prime importance. Our findings reveal that poly(ADP-ribose) polymerase 2 (PARP2) is involved in DSBR pathway choice independently of its PAR synthesis activity. We show that PARP2 favors repair by homologous recombination (HR), single strand annealing (SSA) and alternative-end joining (A-EJ) rather than the C-EJ pathway and increases the deletion sizes at A-EJ junctions. We demonstrate that PARP2 specifically limits the accumulation of the resection barrier factor 53BP1 at DNA damage sites, allowing efficient CtIP-dependent DNA end-resection. Collectively, we have identified a new PARP2 function, independent of its PAR synthesis activity, which directs DSBs toward resection-dependent repair pathways.
format Online
Article
Text
id pubmed-5716083
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-57160832017-12-08 PARP2 controls double-strand break repair pathway choice by limiting 53BP1 accumulation at DNA damage sites and promoting end-resection Fouquin, Alexis Guirouilh-Barbat, Josée Lopez, Bernard Hall, Janet Amor-Guéret, Mounira Pennaneach, Vincent Nucleic Acids Res Genome Integrity, Repair and Replication Double strand breaks (DSBs) are one of the most toxic lesions to cells. DSB repair by the canonical non-homologous end-joining (C-EJ) pathway involves minor, if any, processing of the broken DNA-ends, whereas the initiation of DNA resection channels the broken-ends toward DNA repair pathways using various lengths of homology. Mechanisms that control the resection initiation are thus central to the regulation to the choice of DSB repair pathway. Therefore, understanding the mechanisms which regulate the initiation of DNA end-resection is of prime importance. Our findings reveal that poly(ADP-ribose) polymerase 2 (PARP2) is involved in DSBR pathway choice independently of its PAR synthesis activity. We show that PARP2 favors repair by homologous recombination (HR), single strand annealing (SSA) and alternative-end joining (A-EJ) rather than the C-EJ pathway and increases the deletion sizes at A-EJ junctions. We demonstrate that PARP2 specifically limits the accumulation of the resection barrier factor 53BP1 at DNA damage sites, allowing efficient CtIP-dependent DNA end-resection. Collectively, we have identified a new PARP2 function, independent of its PAR synthesis activity, which directs DSBs toward resection-dependent repair pathways. Oxford University Press 2017-12-01 2017-10-03 /pmc/articles/PMC5716083/ /pubmed/29036662 http://dx.doi.org/10.1093/nar/gkx881 Text en © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Genome Integrity, Repair and Replication
Fouquin, Alexis
Guirouilh-Barbat, Josée
Lopez, Bernard
Hall, Janet
Amor-Guéret, Mounira
Pennaneach, Vincent
PARP2 controls double-strand break repair pathway choice by limiting 53BP1 accumulation at DNA damage sites and promoting end-resection
title PARP2 controls double-strand break repair pathway choice by limiting 53BP1 accumulation at DNA damage sites and promoting end-resection
title_full PARP2 controls double-strand break repair pathway choice by limiting 53BP1 accumulation at DNA damage sites and promoting end-resection
title_fullStr PARP2 controls double-strand break repair pathway choice by limiting 53BP1 accumulation at DNA damage sites and promoting end-resection
title_full_unstemmed PARP2 controls double-strand break repair pathway choice by limiting 53BP1 accumulation at DNA damage sites and promoting end-resection
title_short PARP2 controls double-strand break repair pathway choice by limiting 53BP1 accumulation at DNA damage sites and promoting end-resection
title_sort parp2 controls double-strand break repair pathway choice by limiting 53bp1 accumulation at dna damage sites and promoting end-resection
topic Genome Integrity, Repair and Replication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716083/
https://www.ncbi.nlm.nih.gov/pubmed/29036662
http://dx.doi.org/10.1093/nar/gkx881
work_keys_str_mv AT fouquinalexis parp2controlsdoublestrandbreakrepairpathwaychoicebylimiting53bp1accumulationatdnadamagesitesandpromotingendresection
AT guirouilhbarbatjosee parp2controlsdoublestrandbreakrepairpathwaychoicebylimiting53bp1accumulationatdnadamagesitesandpromotingendresection
AT lopezbernard parp2controlsdoublestrandbreakrepairpathwaychoicebylimiting53bp1accumulationatdnadamagesitesandpromotingendresection
AT halljanet parp2controlsdoublestrandbreakrepairpathwaychoicebylimiting53bp1accumulationatdnadamagesitesandpromotingendresection
AT amorgueretmounira parp2controlsdoublestrandbreakrepairpathwaychoicebylimiting53bp1accumulationatdnadamagesitesandpromotingendresection
AT pennaneachvincent parp2controlsdoublestrandbreakrepairpathwaychoicebylimiting53bp1accumulationatdnadamagesitesandpromotingendresection