Journal
SCIENCE SIGNALING
Volume 3, Issue 119, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2000781
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Funding
- NCI NIH HHS [P30 CA033572, P30 CA033572-27] Funding Source: Medline
- NIDCR NIH HHS [R01DE10742, R01 DE014183-08, R01 DE010742-16, R01DE14183, R01 DE014183, R01 DE010742] Funding Source: Medline
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Kruppel-associated box (KRAB) domain-associated protein 1 [KAP1, also known as transcription intermediary factor-1 beta (TIF1 beta)] is a ubiquitous transcriptional co-repressor that is susceptible to phosphorylation at Ser(824) by ataxia-telangiectasia mutated (ATM) and to modification by small ubiquitin-like modifying (SUMO) proteins. Here, we found that, whereas the protein phosphatase 1 alpha isoform (PP1 alpha) directly interacted with KAP1 under basal conditions, PP1 beta interacted with KAP1 only in response to genotoxic stress. Changes in the abundance of PP1 alpha or PP1b had differential effects on the phosphorylation and SUMOylation states of KAP1 under basal conditions and in response to DNA double-strand breaks (DSBs). Chromatin immunoprecipitation and re-immunoprecipitation experiments revealed that PP1 alpha and PP1 beta were recruited to KAP1 with different kinetics before and after the induction of DNA DSBs, which provided a mechanistic basis for the switch in the phosphorylation and SUMOylation states of KAP1. PP1 beta-dependent SUMOylation of KAP1 occurred by mechanisms that were dependent and independent of the phosphorylation status of Ser(824). We posit a mechanism whereby the combined actions of PP1 alpha and PP1 beta cause dephosphorylation of KAP1 at Ser(824) and assure its SUMOylation to counter the effect of ATM, thereby regulating the transcription of KAP1 target genes in unstressed and stressed cells.
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