Mus81-Mms4 endonuclease is an Esc2-STUbL-Cullin8 mitotic substrate impacting on genome integrity

Anja Waizenegger, Madhusoodanan Urulangodi, Carl P. Lehmann, Teresa Anne Clarisse Reyes, Irene Saugar, José Antonio Tercero, Barnabas Szakal and Dana Branzei ()
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Anja Waizenegger: IFOM, the FIRC Institute of Molecular Oncology
Madhusoodanan Urulangodi: IFOM, the FIRC Institute of Molecular Oncology
Carl P. Lehmann: Centro de Biología Molecular Severo Ochoa (CSIC/UAM)
Teresa Anne Clarisse Reyes: IFOM, the FIRC Institute of Molecular Oncology
Irene Saugar: Centro de Biología Molecular Severo Ochoa (CSIC/UAM)
José Antonio Tercero: Centro de Biología Molecular Severo Ochoa (CSIC/UAM)
Barnabas Szakal: IFOM, the FIRC Institute of Molecular Oncology
Dana Branzei: IFOM, the FIRC Institute of Molecular Oncology

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract The Mus81-Mms4 nuclease is activated in G2/M via Mms4 phosphorylation to allow resolution of persistent recombination structures. However, the fate of the activated phosphorylated Mms4 remains unknown. Here we find that Mms4 is engaged by (poly)SUMOylation and ubiquitylation and targeted for proteasome degradation, a process linked to the previously described Mms4 phosphorylation cycle. Mms4 is a mitotic substrate for the SUMO-Targeted Ubiquitin ligase Slx5/8, the SUMO-like domain-containing protein Esc2, and the Mms1-Cul8 ubiquitin ligase. In the absence of these activities, phosphorylated Mms4 accumulates on chromatin in an active state in the next G1, subsequently causing abnormal processing of replication-associated recombination intermediates and delaying the activation of the DNA damage checkpoint. Mus81-Mms4 mutants that stabilize phosphorylated Mms4 have similar detrimental effects on genome integrity. Overall, our findings highlight a replication protection function for Esc2-STUbL-Cul8 and emphasize the importance for genome stability of resetting phosphorylated Mms4 from one cycle to another.

Date: 2020
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DOI: 10.1038/s41467-020-19503-4

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