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Cdk1-dependent regulation of the Mre11 complex couples DNA repair pathways to
cell cycle progression
#MMPMID24553123
Simoneau A
; Robellet X
; Ladouceur AM
; D'Amours D
Cell Cycle
2014[]; 13
(7
): 1078-90
PMID24553123
show ga
Homologous recombination (HR) and non-homologous end joining (NHEJ) are the main
pathways ensuring the repair of DNA double-stranded breaks (DSBs) in eukaryotes.
It has long been known that cell cycle stage is a major determinant of the type
of pathway used to repair DSBs in vivo. However, the mechanistic basis for the
cell cycle regulation of the DNA damage response is still unclear. Here we show
that a major DSB sensor, the Mre11-Rad50-Xrs2 (MRX) complex, is regulated by cell
cycle-dependent phosphorylation specifically in mitosis. This modification
depends on the cyclin-dependent kinase Cdc28/Cdk1, and abrogation of Xrs2 and
Mre11 phosphorylation results in a marked preference for DSB repair through NHEJ.
Importantly, we show that phosphorylation of the MRX complex after DNA damage and
during mitosis are regulated independently of each other by Tel1/ATM and
Cdc28/Cdk1 kinases. Collectively, our results unravel an intricate network of
phosphoregulatory mechanisms that act through the MRX complex to modulate DSB
repair efficiency during mitosis.
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