Dynamics of RIF1 SUMOylation is regulated by PIAS4 in the maintenance of Genomic Stability.

RIF1 plays a key role in inhibiting DNA end resection and promoting NHEJ mediated DNA double stand break repair in G1. However, whether SUMOlyation may regulate RIF1 functions is still largely unknown. Here, we report that RIF1 is SUMOlyated in response to DNA damage. We identified PIAS4 as the primary SUMO E3 ligase required for the SUMOylation of RIF1 protein. Mammalian cells compromised of PIAS4 expression, show impaired RIF1 SUMOylation and defective for the disassembly of DNA damage responsive RIF1 foci. Mechanistically, we show that PIAS4 knockdown abrogates UHRF1-dependent ubiquitination of RIF1, compromising RIF1 protein turnover. We detected intense RPA foci that colocalize with RIF1 foci in PIAS4 knockdown cells. These data highlight an important role of PIAS4-dependent regulation of RIF1, likely mediated by SUMOylation, in the disassembly of RIF1 DNA damage response (DDR) foci. We propose that unresolved RIF1 protein at sites of DNA damage in PIAS4-depleted cells largely accumulates in S phase, and subsequently leads to DNA double strand breaks. Therefore, PIAS4 promotes genomic stability by regulating the timely removal of RIF1 from sites of DNA damage.

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