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Rad51-mediated replication of damaged templates relies on monoSUMOylated DDK kinase

Author

Listed:
  • Chinnu Rose Joseph

    (IFOM, Istituto Fondazione di Oncologia Molecolare)

  • Sabrina Dusi

    (IFOM, Istituto Fondazione di Oncologia Molecolare)

  • Michele Giannattasio

    (IFOM, Istituto Fondazione di Oncologia Molecolare
    Dipartimento di Oncologia ed Emato-Oncologia)

  • Dana Branzei

    (IFOM, Istituto Fondazione di Oncologia Molecolare
    Consiglio Nazionale delle Ricerche (IGM-CNR))

Abstract

DNA damage tolerance (DDT), activated by replication stress during genome replication, is mediated by translesion synthesis and homologous recombination (HR). Here we uncover that DDK kinase, essential for replication initiation, is critical for replication-associated recombination-mediated DDT. DDK relies on its multi-monoSUMOylation to facilitate HR-mediated DDT and optimal retention of Rad51 recombinase at replication damage sites. Impairment of DDK kinase activity, reduced monoSUMOylation and mutations in the putative SUMO Interacting Motifs (SIMs) of Rad51 impair replication-associated recombination and cause fork uncoupling with accumulation of large single-stranded DNA regions at fork branching points. Notably, genetic activation of salvage recombination rescues the uncoupled fork phenotype but not the recombination-dependent gap-filling defect of DDK mutants, revealing that the salvage recombination pathway operates preferentially proximal to fork junctions at stalled replication forks. Overall, we uncover that monoSUMOylated DDK acts with Rad51 in an axis that prevents replication fork uncoupling and mediates recombination-dependent gap-filling.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30215-9
    DOI: 10.1038/s41467-022-30215-9
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    References listed on IDEAS

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    1. Malgorzata Bzymek & Nathaniel H. Thayer & Steve D. Oh & Nancy Kleckner & Neil Hunter, 2010. "Double Holliday junctions are intermediates of DNA break repair," Nature, Nature, vol. 464(7290), pages 937-941, April.
    2. Philipp Stelter & Helle D. Ulrich, 2003. "Control of spontaneous and damage-induced mutagenesis by SUMO and ubiquitin conjugation," Nature, Nature, vol. 425(6954), pages 188-191, September.
    3. Dana Branzei & Fabio Vanoli & Marco Foiani, 2008. "SUMOylation regulates Rad18-mediated template switch," Nature, Nature, vol. 456(7224), pages 915-920, December.
    4. Sumedha Agashe & Chinnu Rose Joseph & Teresa Anne Clarisse Reyes & Demis Menolfi & Michele Giannattasio & Anja Waizenegger & Barnabas Szakal & Dana Branzei, 2021. "Smc5/6 functions with Sgs1-Top3-Rmi1 to complete chromosome replication at natural pause sites," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    5. Ken’Ichi Mizuno & Izumi Miyabe & Stephanie A. Schalbetter & Antony M. Carr & Johanne M. Murray, 2013. "Recombination-restarted replication makes inverted chromosome fusions at inverted repeats," Nature, Nature, vol. 493(7431), pages 246-249, January.
    6. 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.
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    1. Lorenzo Galanti & Martina Peritore & Robert Gnügge & Elda Cannavo & Johannes Heipke & Maria Dilia Palumbieri & Barbara Steigenberger & Lorraine S. Symington & Petr Cejka & Boris Pfander, 2024. "Dbf4-dependent kinase promotes cell cycle controlled resection of DNA double-strand breaks and repair by homologous recombination," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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