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Chk1 inhibits replication factory activation but allows dormant origin firing in existing factories
- Source :
- The Journal of Cell Biology
- Publication Year :
- 2010
- Publisher :
- Rockefeller University Press, 2010.
-
Abstract
- At low levels of replication stress, Chk1 favors resolving problems at stalled replication forks over initiating origin firing in unreplicated areas of the genome.<br />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.
- Subjects :
- Cyclin A
Cell Cycle Proteins
Ataxia Telangiectasia Mutated Proteins
chemistry.chemical_compound
0302 clinical medicine
Hydroxyurea
RNA, Small Interfering
Checkpoint Kinase 2
Research Articles
Genetics
0303 health sciences
biology
Carbocyanines
Cyclin-Dependent Kinases
Cell biology
030220 oncology & carcinogenesis
DNA Replication
Aphidicolin
Replication Origin
Protein Serine-Threonine Kinases
Origin of replication
Models, Biological
Article
Cell Line
03 medical and health sciences
Caffeine
Cell Line, Tumor
Proliferating Cell Nuclear Antigen
Roscovitine
Humans
CHEK1
Protein Kinase Inhibitors
030304 developmental biology
Cyclin-Dependent Kinase 2
DNA replication
DNA
Cell Biology
Fibroblasts
DNA Replication Fork
enzymes and coenzymes (carbohydrates)
Bromodeoxyuridine
chemistry
Gamma Rays
Purines
Checkpoint Kinase 1
biology.protein
Deoxyuracil Nucleotides
Protein Kinases
DNA Damage
Subjects
Details
- ISSN :
- 15408140 and 00219525
- Volume :
- 191
- Database :
- OpenAIRE
- Journal :
- Journal of Cell Biology
- Accession number :
- edsair.doi.dedup.....6e61497167e6f3ac5cd53545ff5ca98e