Chk1 regulates the density of active replication origins during the vertebrate S phase.
The checkpoint kinase 1 (Chk1) preserves genome integrity when replication is performed on damaged templates. Recently, Chk1 has also been implicated in regulating different aspects of unperturbed S phase. Using mammalian and avian cells with compromised Chk1 activity, we show that an increase in active replicons compensates for inefficient DNA polymerisation. In the absence of damage, loss of Chk1 activity correlates with the frequent stalling and, possibly, collapse of active forks and activation of adjacent, previously suppressed, origins. In human cells, super-activation of replication origins is restricted to pre-existing replication factories. In avian cells, in contrast, Chk1 deletion also correlates with the super-activation of replication factories and loss of temporal continuity in the replication programme. The same phenotype is induced in wild-type avian cells when Chk1 or ATM/ATR is inhibited. These observations show that Chk1 regulates replication origin activation and contributes to S-phase progression in somatic vertebrate cells.
Maya-Mendoza
Apolinar
A
Faculty of Life Sciences, University of Manchester, MIB, Manchester, UK.
Petermann
Eva
E
Gillespie
David A F
DA
Caldecott
Keith W
KW
Jackson
Dean A
DA
D000818:Animals; D001973:Bromodeoxyuridine; D002110:Caffeine / Q000494:pharmacology; D000071877:Checkpoint Kinase 1; D002645:Chickens; D004261:DNA Replication / Q000235:genetics* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D011494:Protein Kinases / Q000378:metabolism*; D018741:Replication Origin / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D012093:Replicon / Q000235:genetics*; D016196:S Phase / Q000235:genetics* / Q000502:physiology
D002110:Caffeine; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D001973:Bromodeoxyuridine