Cdk1 uncouples CtIP-dependent resection and Rad51 filament formation during M-phase double-strand break repair

Abstract

M-phase DNA double-strand break repair differs from S-phase repair caused by the action of Cdk1, which prevents RPA-bound single-stranded DNA from activating classical DNA repair pathways.

CtIP-mediated resection is essential for viability and can operate independently of BRCA1

“…These conclusions were based on the findings that BRCA1-deficient cells exhibit a mild decrease in IR-induced RPA focus formation (Chen et al, 2008;Escribano-Díaz et al, 2013), that BRCA1 and CtIP inhibit RIF1 end-blocking activity in S/G2 (Escribano-Díaz et al, 2013;Zimmermann et al, 2013), and that cells expressing CtIP-327A are defective in HR (Yun and Hiom, 2009). However, subsequent studies in chicken (Nakamura et al, 2010), frog (Peterson et al, 2011), and mouse cells ; analogous to our CtIPnull cells reconstituted with CtIP-S327A), and direct measurements of gene conversion (Chandramouly et al, 2013), argue that the CtIP-BRCA1 interaction is dispensable for HR. Moreover, our finding that restoration of HR in BRCA1-53BP1-deficient cells and increased resection that occurs in the absence of 53BP1 are CtIP dependent, demonstrates that CtIP-mediated resection is BRCA1 independent.…”

End Resection at Double-Strand Breaks: Mechanism and Regulation

“…These studies identified the Mre11-Rad50-Xrs2 (MRX) complex, Sae2, Exo1, Replication Protein A (RPA), Sgs1, and Dna2 as key factors for 5 0 -3 0 end resection, and their activities are conserved in other eukaryotes investigated (human NBS1, CtIP, and BLM are the functional orthologs of Xrs2, Sae2, and Sgs1, respectively) (Gravel et al 2008;Mimitou and Symington 2008;Zhu et al 2008;Nimonkar et al 2011;Peterson et al 2011;Karanja et al 2012;Chen et al 2013). A widely accepted view is for MRX/N and Sae2/CtIP to initiate end resection by endonucleolytic cleavage of the 5 0 ends internal to break ends releasing oligonucleotides.…”

Nek1 kinase associates with ATR–ATRIP and primes ATR for efficient DNA damage signaling

“…Although the ATR-Chk1 kinase cascade is clearly the backbone of the ATR signaling pathway, several other protein kinases, such as ATM (6,7), CDKs (cyclin-dependent kinases) (8)(9)(10), PLK1 (polo-like kinase) (11)(12)(13)(14), AKT (15,16), and casein kinases (17,18), have been implicated in tuning the strength and dynamics of ATR signaling in different contexts. The effects of these kinases on ATR signaling suggest that the ATR pathway is intertwined with other signaling pathways and cellular programs.…”