Phosphorylation by CK2 regulates MUS81/EME1 in mitosis and after replication stress

Anita Palma, Giusj Monia Pugliese, Ivana Murfuni, Veronica Marabitti, Eva Malacaria, Sara Rinalducci, Anna Minoprio, Massimo Sanchez, Filomena Mazzei, Lello Zolla, Annapaola Franchitto, Pietro Pichierri

Research output: Contribution to journalArticle

Abstract

The MUS81 complex is crucial for preserving genome stability through the resolution of branched DNA intermediates in mitosis. However, untimely activation of the MUS81 complex in S-phase is dangerous. Little is known about the regulation of the human MUS81 complex and how deregulated activation affects chromosome integrity. Here, we show that the CK2 kinase phosphorylates MUS81 at Serine 87 in late-G2/mitosis, and upon mild replication stress. Phosphorylated MUS81 interacts with SLX4, and this association promotes the function of the MUS81 complex. In line with a role in mitosis, phosphorylation at Serine 87 is suppressed in S-phase and is mainly detected in the MUS81 molecules associated with EME1. Loss of CK2-dependent MUS81 phosphorylation contributes modestly to chromosome integrity, however, expression of the phosphomimic form induces DSBs accumulation in S-phase, because of unscheduled targeting of HJ-like DNA intermediates, and generates a wide chromosome instability phenotype. Collectively, our findings describe a novel regulatory mechanism controlling the MUS81 complex function in human cells. Furthermore, they indicate that, genome stability depends mainly on the ability of cells to counteract targeting of branched intermediates by the MUS81/EME1 complex in S-phase, rather than on a correct MUS81 function in mitosis.

Original languageEnglish
Pages (from-to)5109-5124
Number of pages16
JournalNucleic Acids Research
Volume46
Issue number10
DOIs
Publication statusPublished - Jan 1 2018

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ASJC Scopus subject areas

  • Genetics

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