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Abstract
Krüppel-associated box (KRAB) domain–associated protein 1 [KAP1, also known as transcription intermediary factor–1β (TIF1β)] is a ubiquitous transcriptional co-repressor that is susceptible to phosphorylation at Ser824 by ataxia-telangiectasia mutated (ATM) and to modification by small ubiquitin-like modifying (SUMO) proteins. Here, we found that, whereas the protein phosphatase 1α isoform (PP1α) directly interacted with KAP1 under basal conditions, PP1β interacted with KAP1 only in response to genotoxic stress. Changes in the abundance of PP1α or PP1β 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 PP1α and PP1β 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. PP1β-dependent SUMOylation of KAP1 occurred by mechanisms that were dependent and independent of the phosphorylation status of Ser824. We posit a mechanism whereby the combined actions of PP1α and PP1β cause dephosphorylation of KAP1 at Ser824 and assure its SUMOylation to counter the effect of ATM, thereby regulating the transcription of KAP1 target genes in unstressed and stressed cells.
