title: Chk1 inhibits replication factory activation but allows dormant origin firing in existing factories.
abstract: Replication origins are licensed by loading MCM2-7 hexamers before entry into S phase. However, only ∼10% of licensed origins are normally used in S phase, with the others remaining dormant. When fork progression is inhibited, dormant origins initiate nearby to ensure that all of the DNA is eventually replicated. In apparent contrast, replicative stress activates ataxia telangiectasia and rad-3-related (ATR) and Chk1 checkpoint kinases that inhibit origin firing. In this study, we show that at low levels of replication stress, ATR/Chk1 predominantly suppresses origin initiation by inhibiting the activation of new replication factories, thereby reducing the number of active factories. At the same time, inhibition of replication fork progression allows dormant origins to initiate within existing replication factories. The inhibition of new factory activation by ATR/Chk1 therefore redirects replication toward active factories where forks are inhibited and away from regions that have yet to start replication. This minimizes the deleterious consequences of fork stalling and prevents similar problems from arising in unreplicated regions of the genome.
authors.affiliation: Wellcome Trust Centre for Gene Regulation and Expression, University of Dundee, Dundee DD1 5EH, Scotland, UK.
authors.forename: Xin Quan
authors.initials: XQ
authors.lastname: Ge
authors.forename: J Julian
authors.initials: JJ
authors.lastname: Blow
mesh_terms: D016590:Aphidicolin / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology; D002232:Carbocyanines / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D019925:Cyclin A / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004247:DNA / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology; D004261:DNA Replication / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D003856:Deoxyuracil Nucleotides / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005720:Gamma Rays; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D008954:Models, Biological; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D018741:Replication Origin / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D000077546:Roscovitine
chemical_list: C088941:3'-deoxy-5-(cyanine dye 3)uridine 5'-trisphosphate; D002232:Carbocyanines; D018797:Cell Cycle Proteins; D019925:Cyclin A; D003856:Deoxyuracil Nucleotides; C489423:MCM5 protein, human; D018809:Proliferating Cell Nuclear Antigen; D047428:Protein Kinase Inhibitors; D011687:Purines; D034741:RNA, Small Interfering; D000077546:Roscovitine; D016590:Aphidicolin; D002110:Caffeine; D004247:DNA; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D001973:Bromodeoxyuridine; D006918:Hydroxyurea