Deletion of BRCA2 exon 27 causes defects in response to both stalled and collapsed replication forks

Mutation Research
Tae Moon KimPaul Hasty

Abstract

BRCA2 is a tumor suppressor that maintains genomic integrity through double strand break (DSB) repair and replication fork protection. The BRC motifs and an exon 27-encoded domain (Ex27) of BRCA2 interact with the recombinase RAD51 to, respectively, facilitate the formation and stability of a RAD51 filament on single strand DNA. The BRC-RAD51 associations enable DSB repair while the Ex27-RAD51 association protects the nascent replication strand from MRE11-mediated degradation. MRE11 is a nuclease that facilitates the generation of 3' overhangs needed for homologous recombination (HR)-mediated DSB repair. Here we report the dynamics of replication fork maintenance in mouse embryonic stem (ES) cells deleted for Ex27 (brca2(lex1/lex2)) after exposure to hydroxyurea (HU) that depletes nucleotides. HU conditions were varied from mild to severe. Mild conditions induce an ATR-response to replication fork stalling while severe conditions induce a DNA-PKCS-response to replication fork collapse and a DSB. These responses were differentiated by replication protein A (RPA) phosphorylation. We found that Ex27 deletion reduced MRE11 localization to stalled, but not collapsed, replication forks and that Ex27-deletion caused a proportionately ...Continue Reading

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Citations

Jul 24, 2015·Molecular & Cellular Oncology·Paul Hasty, Cristina Montagna
Sep 2, 2015·Nucleic Acids Research·Ann C ParplysClaudia Wiese
Jun 25, 2016·Oncotarget·Mi Young SonPaul Hasty
Nov 29, 2020·Genes, Chromosomes & Cancer·Rayhaan M M AliKienan I Savage

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