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Rad52 prevents excessive replication fork reversal and protects from nascent strand degradation

Author

Listed:
  • Eva Malacaria

    (Istituto Superiore di Sanità)

  • Giusj Monia Pugliese

    (Istituto Superiore di Sanità)

  • Masayoshi Honda

    (University of Iowa)

  • Veronica Marabitti

    (Istituto Superiore di Sanità)

  • Francesca Antonella Aiello

    (Istituto Superiore di Sanità)

  • Maria Spies

    (University of Iowa)

  • Annapaola Franchitto

    (Istituto Superiore di Sanità)

  • Pietro Pichierri

    (Istituto Superiore di Sanità
    Istituto Nazionale Biostrutture e Biosistemi)

Abstract

Stabilisation of stalled replication forks prevents excessive fork reversal and their pathological degradation, which can undermine genome integrity. Here we investigate a physiological role of RAD52 at stalled replication forks by using human cell models depleted of RAD52, a specific small-molecule inhibitor of the RAD52-ssDNA interaction, in vitro and single-molecule analyses. We demonstrate that RAD52 prevents excessive degradation of reversed replication forks by MRE11. Mechanistically, RAD52 binds to the stalled replication fork, promotes its occlusion and counteracts loading of SMARCAL1 in vitro and in vivo. Loss of the RAD52 function results in a slightly-defective replication restart, persistence of under-replicated regions and chromosome instability. Moreover, the RAD52-inhibited cells rely on RAD51 for completion of replication and viability upon replication arrest. Collectively, our data suggest an unexpected gatekeeper mechanism by which RAD52 limits excessive remodelling of stalled replication forks, thus indirectly assisting RAD51 and BRCA2 in protecting forks from unscheduled degradation and preventing genome instability.

Suggested Citation

  • Eva Malacaria & Giusj Monia Pugliese & Masayoshi Honda & Veronica Marabitti & Francesca Antonella Aiello & Maria Spies & Annapaola Franchitto & Pietro Pichierri, 2019. "Rad52 prevents excessive replication fork reversal and protects from nascent strand degradation," Nature Communications, Nature, vol. 10(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09196-9
    DOI: 10.1038/s41467-019-09196-9
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    Cited by:

    1. Arindam Datta & Kajal Biswas & Joshua A. Sommers & Haley Thompson & Sanket Awate & Claudia M. Nicolae & Tanay Thakar & George-Lucian Moldovan & Robert H. Shoemaker & Shyam K. Sharan & Robert M. Brosh, 2021. "WRN helicase safeguards deprotected replication forks in BRCA2-mutated cancer cells," Nature Communications, Nature, vol. 12(1), pages 1-22, December.
    2. George E. Ronson & Katarzyna Starowicz & Elizabeth J. Anthony & Ann Liza Piberger & Lucy C. Clarke & Alexander J. Garvin & Andrew D. Beggs & Celina M. Whalley & Matthew J. Edmonds & James F. J. Beesle, 2023. "Mechanisms of synthetic lethality between BRCA1/2 and 53BP1 deficiencies and DNA polymerase theta targeting," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Frederick Richards & Marta J. Llorca-Cardenosa & Jamie Langton & Sara C. Buch-Larsen & Noor F. Shamkhi & Abhishek Bharadwaj Sharma & Michael L. Nielsen & Nicholas D. Lakin, 2023. "Regulation of Rad52-dependent replication fork recovery through serine ADP-ribosylation of PolD3," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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