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SENP6 regulates localization and nuclear condensation of DNA damage response proteins by group deSUMOylation

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Listed:
  • Laura A. Claessens

    (Leiden University Medical Centre)

  • Matty Verlaan-de Vries

    (Leiden University Medical Centre)

  • Ilona J. Graaf

    (Leiden University Medical Centre)

  • Alfred C. O. Vertegaal

    (Leiden University Medical Centre)

Abstract

The SUMO protease SENP6 maintains genomic stability, but mechanistic understanding of this process remains limited. We find that SENP6 deconjugates SUMO2/3 polymers on a group of DNA damage response proteins, including BRCA1-BARD1, 53BP1, BLM and ERCC1-XPF. SENP6 maintains these proteins in a hypo-SUMOylated state under unstressed conditions and counteracts their polySUMOylation after hydroxyurea-induced stress. Co-depletion of RNF4 leads to a further increase in SUMOylation of BRCA1, BARD1 and BLM, suggesting that SENP6 antagonizes targeting of these proteins by RNF4. Functionally, depletion of SENP6 results in uncoordinated recruitment and persistence of SUMO2/3 at UVA laser and ionizing radiation induced DNA damage sites. Additionally, SUMO2/3 and DNA damage response proteins accumulate in nuclear bodies, in a PML-independent manner driven by multivalent SUMO-SIM interactions. These data illustrate coordinated regulation of SUMOylated DNA damage response proteins by SENP6, governing their timely localization at DNA damage sites and nuclear condensation state.

Suggested Citation

  • Laura A. Claessens & Matty Verlaan-de Vries & Ilona J. Graaf & Alfred C. O. Vertegaal, 2023. "SENP6 regulates localization and nuclear condensation of DNA damage response proteins by group deSUMOylation," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41623-w
    DOI: 10.1038/s41467-023-41623-w
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    References listed on IDEAS

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    1. Yaron Galanty & Rimma Belotserkovskaya & Julia Coates & Sophie Polo & Kyle M. Miller & Stephen P. Jackson, 2009. "Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks," Nature, Nature, vol. 462(7275), pages 935-939, December.
    2. Ramesh Kumar & Román González-Prieto & Zhenyu Xiao & Matty Verlaan-de Vries & Alfred C. O. Vertegaal, 2017. "The STUbL RNF4 regulates protein group SUMOylation by targeting the SUMO conjugation machinery," Nature Communications, Nature, vol. 8(1), pages 1-16, December.
    3. Markus Schick & Le Zhang & Sabine Maurer & Hans Carlo Maurer & Konstandina Isaakaidis & Lara Schneider & Upayan Patra & Kathrin Schunck & Elena Rohleder & Julia Hofstetter & Apoorva Baluapuri & Anna K, 2022. "Genetic alterations of the SUMO isopeptidase SENP6 drive lymphomagenesis and genetic instability in diffuse large B-cell lymphoma," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    4. Frauke Liebelt & Nicolette S. Jansen & Sumit Kumar & Ekaterina Gracheva & Laura A. Claessens & Matty Verlaan-de Vries & Edwin Willemstein & Alfred C. O. Vertegaal, 2019. "The poly-SUMO2/3 protease SENP6 enables assembly of the constitutive centromere-associated network by group deSUMOylation," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
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