Journal
JOURNAL OF CELL SCIENCE
Volume 118, Issue 1, Pages 1-6Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.01626
Keywords
DNA damage; cell-cycle checkpoint control; ATR; ATM; Chk1
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Funding
- NATIONAL CANCER INSTITUTE [R01CA100076, R56CA100076] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM062193] Funding Source: NIH RePORTER
- NCI NIH HHS [CA100076] Funding Source: Medline
- NIGMS NIH HHS [GM062193] Funding Source: Medline
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Cells mount a coordinated response to DNA damage, activating DNA repair pathways and cell-cycle checkpoint pathways to allow time for DNA repair to occur. In human cells, checkpoint responses can be divided into p53-dependent and p53-independent pathways, the latter being predominant in G2 phase of the cell cycle. The p53-independent pathway involves a phosphorylation cascade that activates the Chk1 effector kinase and induces G2 arrest through inhibitory tyrosine phosphorylation of Cdc2. At the top of this cascade are the ATR and ATM kinases. How ATM and ATR recognize DNA damage and activate this checkpoint pathway is only beginning to emerge. Single-stranded DNA, a result of stalled DNA replication or processing of chromosomal lesions, appears to be central to the activation of ATR. The recruitment of replication protein A to single-stranded DNA facilitates the recruitment of several complexes of checkpoint proteins. In this context, ATR is activated and then phosphorylates the C-terminus of Chk1, activating it to enforce a block to mitotic entry.
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