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RIF1 promotes replication fork protection and efficient restart to maintain genome stability

Author

Listed:
  • Chirantani Mukherjee

    (Erasmus University Medical Center)

  • Vivek Tripathi

    (Erasmus University Medical Center)

  • Eleni Maria Manolika

    (Erasmus University Medical Center)

  • Anne Margriet Heijink

    (University Medical Center Groningen, University of Groningen
    Mount Sinai Hospital)

  • Giulia Ricci

    (Erasmus University Medical Center)

  • Sarra Merzouk

    (Erasmus University Medical Center)

  • H. Rudolf Boer

    (University Medical Center Groningen, University of Groningen)

  • Jeroen Demmers

    (Erasmus University Medical Center)

  • Marcel A. T. M. Vugt

    (University Medical Center Groningen, University of Groningen)

  • Arnab Ray Chaudhuri

    (Erasmus University Medical Center)

Abstract

Homologous recombination (HR) and Fanconi Anemia (FA) pathway proteins in addition to their DNA repair functions, limit nuclease-mediated processing of stalled replication forks. However, the mechanism by which replication fork degradation results in genome instability is poorly understood. Here, we identify RIF1, a non-homologous end joining (NHEJ) factor, to be enriched at stalled replication forks. Rif1 knockout cells are proficient for recombination, but displayed degradation of reversed forks, which depends on DNA2 nuclease activity. Notably, RIF1-mediated protection of replication forks is independent of its function in NHEJ, but depends on its interaction with Protein Phosphatase 1. RIF1 deficiency delays fork restart and results in exposure of under-replicated DNA, which is the precursor of subsequent genomic instability. Our data implicate RIF1 to be an essential factor for replication fork protection, and uncover the mechanisms by which unprotected DNA replication forks can lead to genome instability in recombination-proficient conditions.

Suggested Citation

  • Chirantani Mukherjee & Vivek Tripathi & Eleni Maria Manolika & Anne Margriet Heijink & Giulia Ricci & Sarra Merzouk & H. Rudolf Boer & Jeroen Demmers & Marcel A. T. M. Vugt & Arnab Ray Chaudhuri, 2019. "RIF1 promotes replication fork protection and efficient restart to maintain genome stability," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11246-1
    DOI: 10.1038/s41467-019-11246-1
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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. Hannah L. Mackay & Helen R. Stone & George E. Ronson & Katherine Ellis & Alexander Lanz & Yara Aghabi & Alexandra K. Walker & Katarzyna Starowicz & Alexander J. Garvin & Patrick Van Eijk & Stefan A. K, 2024. "USP50 suppresses alternative RecQ helicase use and deleterious DNA2 activity during replication," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Anchel de Jaime-Soguero & Janina Hattemer & Anja Bufe & Alexander Haas & Jeroen Berg & Vincent Batenburg & Biswajit Das & Barbara Marco & Stefania Androulaki & Nicolas Böhly & Jonathan J. M. Landry & , 2024. "Developmental signals control chromosome segregation fidelity during pluripotency and neurogenesis by modulating replicative stress," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    4. Inés Paniagua & Zainab Tayeh & Mattia Falcone & Santiago Hernández Pérez & Aurora Cerutti & Jacqueline J. L. Jacobs, 2022. "MAD2L2 promotes replication fork protection and recovery in a shieldin-independent and REV3L-dependent manner," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Cuige Zhu & Mari Iwase & Ziqian Li & Faliang Wang & Annabel Quinet & Alessandro Vindigni & Jieya Shao, 2022. "Profilin-1 regulates DNA replication forks in a context-dependent fashion by interacting with SNF2H and BOD1L," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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