High levels of RAD51 perturb DNA replication elongation and cause unscheduled origin firing due to impaired CHK1 activation

Cell Cycle
Ann Christin ParplysKerstin Borgmann

Abstract

In response to replication stress ATR signaling through CHK1 controls the intra-S checkpoint and is required for the maintenance of genomic integrity. Homologous recombination (HR) comprises a series of interrelated pathways that function in the repair of DNA double strand breaks and interstrand crosslinks. In addition, HR, with its key player RAD51, provides critical support for the recovery of stalled forks during replication. High levels of RAD51 are regularly found in various cancers, yet little is known about the effect of the increased RAD51 expression on intra-S checkpoint signaling. Here, we describe a role for RAD51 in driving genomic instability caused by impaired replication and intra-S mediated CHK1 signaling by studying an inducible RAD51 overexpression model as well as 10 breast cancer cell lines. We demonstrate that an excess of RAD51 decreases I-Sce-I mediated HR despite formation of more RAD51 foci. Cells with high RAD51 levels display reduced elongation rates and excessive dormant origin firing during undisturbed growth and after damage, likely caused by impaired CHK1 activation. In consequence, the inability of cells with a surplus of RAD51 to properly repair complex DNA damage and to resolve replication stre...Continue Reading

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Citations

Nov 29, 2016·Cell Cycle·Antonio AbeytaToshiyasu Taniguchi
Mar 16, 2019·Scientific Reports·Charles X WangAlexander V Mazin
Dec 6, 2018·Biochemical Society Transactions·Darshil R Patel, Robert S Weiss
Feb 13, 2021·Scientific Reports·Tara Al ZubaidiHenning Willers
Feb 1, 2020·Pharmacology & Therapeutics·Erik LauriniSabrina Pricl
Mar 12, 2021·Nucleic Acids Research·Mohamed Elsaid Ashour, Nima Mosammaparast
Apr 10, 2019·Trends in Genetics : TIG·Jun XiaSusan M Rosenberg

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Datasets Mentioned

BETA
MDA-468

Methods Mentioned

BETA
flow cytometry
FACS
transfection
DNA fiber
fluorescence microscopy

Software Mentioned

Optimas
ImageJ
ModFitLT
Prism
GraphPad

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