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

Author

Listed:
  • Anja Waizenegger

    (IFOM, the FIRC Institute of Molecular Oncology)

  • Madhusoodanan Urulangodi

    (IFOM, the FIRC Institute of Molecular Oncology
    Sree Chitra Tirunal Institute for Medical Sciences and Technology (SCTIMST))

  • 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
    Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche (IGM-CNR))

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.

Suggested Citation

  • Anja Waizenegger & Madhusoodanan Urulangodi & Carl P. Lehmann & Teresa Anne Clarisse Reyes & Irene Saugar & José Antonio Tercero & Barnabas Szakal & Dana Branzei, 2020. "Mus81-Mms4 endonuclease is an Esc2-STUbL-Cullin8 mitotic substrate impacting on genome integrity," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19503-4
    DOI: 10.1038/s41467-020-19503-4
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    Cited by:

    1. Joana S. Rodrigues & Miguel Chenlo & Susana B. Bravo & Sihara Perez-Romero & Maria Suarez-Fariña & Tomas Sobrino & Rebeca Sanz-Pamplona & Román González-Prieto & Manuel Narciso Blanco Freire & Ruben N, 2024. "dsRNAi-mediated silencing of PIAS2beta specifically kills anaplastic carcinomas by mitotic catastrophe," Nature Communications, Nature, vol. 15(1), pages 1-30, December.
    2. Chinnu Rose Joseph & Sabrina Dusi & Michele Giannattasio & Dana Branzei, 2022. "Rad51-mediated replication of damaged templates relies on monoSUMOylated DDK kinase," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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