Sequential role of RAD51 paralog complexes in replication fork remodeling and restart.

Nature Communications
Matteo BertiMassimo Lopes

Abstract

Homologous recombination (HR) factors were recently implicated in DNA replication fork remodeling and protection. While maintaining genome stability, HR-mediated fork remodeling promotes cancer chemoresistance, by as-yet elusive mechanisms. Five HR cofactors - the RAD51 paralogs RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3 - recently emerged as crucial tumor suppressors. Albeit extensively characterized in DNA repair, their role in replication has not been addressed systematically. Here, we identify all RAD51 paralogs while screening for modulators of RAD51 recombinase upon replication stress. Single-molecule analysis of fork progression and architecture in isogenic cellular systems shows that the BCDX2 subcomplex restrains fork progression upon stress, promoting fork reversal. Accordingly, BCDX2 primes unscheduled degradation of reversed forks in BRCA2-defective cells, boosting genomic instability. Conversely, the CX3 subcomplex is dispensable for fork reversal, but mediates efficient restart of reversed forks. We propose that RAD51 paralogs sequentially orchestrate clinically relevant transactions at replication forks, cooperatively promoting fork remodeling and restart.

References

Aug 15, 1998·The Journal of Biological Chemistry·D K BishopA Shinohara
Oct 29, 1999·Genes & Development·A J PierceM Jasin
Dec 18, 2001·The Journal of Biological Chemistry·Kristi A MillerJoanna S Albala
Feb 14, 2002·Nucleic Acids Research·Nan LiuLarry H Thompson
Mar 26, 2002·The Journal of Biological Chemistry·Catherine A FrenchJohn Thacker
May 10, 2002·Nucleic Acids Research·Barbara C GodthelpMassgorzata Z Zdzienicka
Apr 30, 2003·Molecular Cell·Judith Henry-MowattKeith W Caldecott
Aug 12, 2005·Nucleic Acids Research·Yasukazu YonetaniMistuyoshi Yamazoe
Dec 24, 2008·The Journal of Cell Biology·Kazuto SugimuraKatsuzumi Okumura
Apr 20, 2010·Nature Genetics·Fiona VazChristopher G Mathew
Aug 21, 2010·Breast Cancer Research : BCR·Mohammad R AkbariSteven A Narod
Nov 26, 2010·Nucleic Acids Research·Dmitry V BugreevAlexander V Mazin
Aug 9, 2011·Nature Genetics·Chey LovedayNazneen Rahman
Dec 24, 2011·Nature Reviews. Cancer·Rohini RoySimon N Powell
Mar 6, 2012·Nature Structural & Molecular Biology·Arnab Ray ChaudhuriMassimo Lopes
Apr 3, 2012·American Journal of Human Genetics·D J ParkM C Southey
Apr 28, 2012·Nature Genetics·Chey LovedayNazneen Rahman
Feb 7, 2013·DNA Repair·Ryan B JensenStephen C Kowalczykowski
Feb 12, 2013·Nature Structural & Molecular Biology·Matteo BertiAlessandro Vindigni
Mar 5, 2013·Nature Structural & Molecular Biology·Cindy FollonierMassimo Lopes
Mar 13, 2013·The Journal of Cell Biology·Kai J NeelsenMassimo Lopes
Jun 12, 2013·Cell Reports·Rémy BétousDavid Cortez
Feb 26, 2015·Nature Reviews. Molecular Cell Biology·Kai J Neelsen, Massimo Lopes
Mar 4, 2015·The Journal of Cell Biology·Saravanabhavan ThangavelAlessandro Vindigni
Mar 4, 2015·The Journal of Cell Biology·Ralph ZellwegerMassimo Lopes
Jun 9, 2015·Molecular Cell·Andrew C KileKarlene A Cimprich
Feb 4, 2016·Nature Structural & Molecular Biology·Matteo Berti, Alessandro Vindigni
Jul 23, 2016·Nature·Arnab Ray ChaudhuriAndré Nussenzweig

❮ Previous
Next ❯

Citations

May 13, 2021·Nucleic Acids Research·Tanay Thakar, George-Lucian Moldovan
Jun 10, 2021·Molecular Cell·Archana KrishnamoorthyDavid Cortez
May 28, 2021·Frontiers in Cell and Developmental Biology·Shan QiuJun Huang
Jul 27, 2021·Current Opinion in Genetics & Development·Hayley L ReinRobert A Baldock
Aug 30, 2021·Current Opinion in Genetics & Development·Yea-Lih Lin, Philippe Pasero
Oct 6, 2021·Bioscience Reports·Kathrin Allkanjari, Robert A Baldock

❮ Previous
Next ❯

Methods Mentioned

BETA
immunoprecipitation
transfection
chromosomal aberrations
transfections

Software Mentioned

DigitalMicrograph
GraphPad Prism7
Olympus ScanR Image Analysis
Spotfire
ImageJ64

Related Concepts

Related Feeds

Breast Cancer: BRCA1 & BRCA2

Mutations involving BRCA1, found on chromosome 17, and BRCA2, found on chromosome 13, increase the risk for specific cancers, such as breast cancer. Discover the last research on breast cancer BRCA1 and BRCA2 here.