STAT-1 facilitates the ATM activated checkpoint pathway following DNA damage
Townsend, Paul A., Cragg, Mark S., Davidson, Sean M., McCormick, James, Barry, Sean, Lawrence, Kevin M., Knight, Richard A., Hubank, Michael, Chen, Phang-Lang, Latchman, David S. and Stephanou, Anastasis (2005) STAT-1 facilitates the ATM activated checkpoint pathway following DNA damage. Journal of Cell Science, 118, (8), 1629-1639. (doi:10.1242/jcs.01728).
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Description/Abstract
STAT-1 plays a role in mediating stress responses to various stimuli and has also been implied to be a tumour suppressor. Here, we report that STAT-1-deficient cells have defects both in intra-S-phase and G2-M checkpoints in response to DNA damage. Interestingly, STAT-1-deficient cells showed reduced Chk2 phosphorylation on threonine 68 (Chk2-T68) following DNA damage, suggesting that STAT-1 might function in the ATM-Chk2 pathway. Moreover, the defects in Chk2-T68 phosphorylation in STAT-1-deficient cells also correlated with reduced degradation of Cdc25A compared with STAT-1-expressing cells after DNA damage. We also show that STAT-1 is required for ATM-dependent phosphorylation of NBS1 and p53 but not for BRCA1 or H2AX phosphorylation following DNA damage. Expression levels of BRCT mediator/adaptor proteins MDC1 and 53BP1, which are required for ATM-mediated pathways, are reduced in cells lacking STAT-1. Enforced expression of MDC1 into STAT-1-deficient cells restored ATM-mediated phosphorylation of downstream substrates. These results imply that STAT-1 plays a crucial role in the DNA-damage-response by regulating the expression of 53BP1 and MDC1, factors known to be important for mediating ATM-dependent checkpoint pathways.
| Item Type: | Article |
|---|---|
| ISSNs: | 0021-9533 (print) |
| Related URLs: | |
| Keywords: | ATM, cell cycle, Chk2, 53BP1, MDC1, STAT-1 |
| Subjects: | R Medicine > RM Therapeutics. Pharmacology R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) Q Science > QH Natural history > QH426 Genetics |
| Divisions: | University Structure - Pre August 2011 > School of Medicine > Cancer Sciences |
| Item ID: | 26646 |
| Date Deposited: | 10 Apr 2006 |
| Last Modified: | 01 Jun 2011 06:29 |
| Contributors: | Townsend, Paul A. (Author) Cragg, Mark S. (Author) Davidson, Sean M. (Author) McCormick, James (Author) Barry, Sean (Author) Lawrence, Kevin M. (Author) Knight, Richard A. (Author) Hubank, Michael (Author) Chen, Phang-Lang (Author) Latchman, David S. (Author) Stephanou, Anastasis (Author) |
| Date: | 2005 |
| Status: | Published |
| Contact Email Address: | a.stephanou@ich.ucl.ac.uk |
| URI: | http://eprints.soton.ac.uk/id/eprint/26646 |
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