CK2 kinase-mediated PHF8 phosphorylation controls TopBP1 stability to regulate DNA replication.

ABSTRACT: ATR functions as a master regulator of the DNA-damage response. ATR activation requires the ATR activator, topoisomerase IIβ-binding protein 1 (TopBP1). However, the underlying mechanism of TopBP1 regulation and how its regulation affects DNA replication remain unknown. Here, we report a specific interaction between TopBP1 and the histone demethylase PHF8. The TopBP1/PHF8 interaction is mediated by the BRCT 7+8 domain of TopBP1 and phosphorylation of PHF8 at Ser854. This interaction is cell-cycle regulated and phosphorylation-dependent. PHF8 is phosphorylated by CK2, which regulates binding of PHF8 to TopBP1. Importantly, PHF8 regulates TopBP1 protein level by preventing its ubiquitination and degradation mediated by the E3 ligase UBR5. Interestingly, PHF8pS854 is likely to contribute to r

SUBMITTER: Feng H 

PROVIDER: S-EPMC7641741 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature