Journal
EMBO JOURNAL
Volume 31, Issue 10, Pages 2403-2415Publisher
WILEY
DOI: 10.1038/emboj.2012.86
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Funding
- NCI [R01CA142698]
- JCRT
- ACS [RSG-12-079-01]
- NIH [CA 009078-34]
- Association for International Cancer Research
- Medical Research Council
- Medical Research Council [G1000050] Funding Source: researchfish
- MRC [G1000050] Funding Source: UKRI
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Protein phosphatase PP4C has been implicated in the DNA damage response (DDR), but its substrates in DDR remain largely unknown. We devised a novel proteomic strategy for systematic identification of proteins dephosphorylated by PP4C and identified KRAB-domain-associated protein 1 (KAP-1) as a substrate. Ionizing radiation leads to phosphorylation of KAP-1 at S824 (via ATM) and at S473 (via CHK2). A PP4C/R3 beta complex interacts with KAP-1 and silencing this complex leads to persistence of phospho-S824 and phospho-S473. We identify a new role for KAP-1 in DDR by showing that phosphorylation of S473 impacts the G2/M checkpoint. Depletion of PP4R3 beta or expression of the phosphomimetic KAP-1 S473 mutant (S473D) leads to a prolonged G2/M checkpoint. Phosphorylation of S824 is necessary for repair of heterochromatic DNA lesions and similar to cells expressing phosphomimetic KAP-1 S824 mutant (S824D), or PP4R3 beta-silenced cells, display prolonged relaxation of chromatin with release of chromatin remodelling protein CHD3. Our results define a new role for PP4-mediated dephosphorylation in the DDR, including the regulation of a previously undescribed function of KAP-1 in checkpoint response. The EMBO Journal (2012) 31, 2403-2415. doi: 10.1038/emboj.2012.86; Published online 10 April 2012
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