XRCC2 Regulates Replication Fork Progression during dNTP Alterations

• Main Authors: Sneha Saxena, Kumar Somyajit, Ganesh Nagaraju
• Format: Article
• Language: English
• Published: Elsevier 2018-12-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S221112471831876X

Summary: RAD51 paralogs are essential for maintenance of genomic integrity through protection of stalled replication forks and homology-directed repair (HDR) of double-strand breaks. Here, we find that a subset of RAD51 paralogs, XRCC2 (FANCU) and its binding partner RAD51D, restrain active DNA synthesis during deoxyribonucleotide triphosphate (dNTP) alterations in a manner independent of HDR. The absence of XRCC2 is associated with increased levels of RRM2, the regulatory subunit of ribonucleotide reductase (RNR), and concomitantly high nucleotide pools, leading to unrestrained fork progression and accumulation of DNA damage during dNTP alterations. Mechanistically, this function is independent of redox signaling and RAD51-mediated fork reversal and is regulated by ataxia-telangiectasia and Rad3-related (ATR) signaling through phosphorylation of XRCC2 (Ser247). Together, these findings identify roles of RAD51 paralogs in the control of replication fork progression and maintenance of genome stability during nucleotide pool alterations. : Coordination between dNTP metabolism and DNA replication is essential to limit replication-associated mutations and tumorigenesis. Here, Saxena et al. identify a dedicated pathway involving a subcomplex of RAD51 paralogs (RAD51D-XRCC2) which modulates replication fork progression as part of ATR signaling and fosters genome integrity during fluctuations in cellular nucleotide pools. Keywords: fork slowing, ribonucleotide reductase, RAD51 paralogs, ATR signaling, replication stress, dNTP pools, genome stability