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The KU-PARP14 axis differentially regulates DNA resection at stalled replication forks by MRE11 and EXO1

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  • Ashna Dhoonmoon

    (The Pennsylvania State University College of Medicine)

  • Claudia M. Nicolae

    (The Pennsylvania State University College of Medicine)

  • George-Lucian Moldovan

    (The Pennsylvania State University College of Medicine)

Abstract

Suppression of nascent DNA degradation has emerged as an essential role of the BRCA pathway in genome protection. In BRCA-deficient cells, the MRE11 nuclease is responsible for both resection of reversed replication forks, and accumulation of single stranded DNA gaps behind forks. Here, we show that the mono-ADP-ribosyltransferase PARP14 is a critical co-factor of MRE11. PARP14 is recruited to nascent DNA upon replication stress in BRCA-deficient cells, and through its catalytic activity, mediates the engagement of MRE11. Loss or inhibition of PARP14 suppresses MRE11-mediated fork degradation and gap accumulation, and promotes genome stability and chemoresistance of BRCA-deficient cells. Moreover, we show that the KU complex binds reversed forks and protects them against EXO1-catalyzed degradation. KU recruits the PARP14-MRE11 complex, which initiates partial resection to release KU and allow long-range resection by EXO1. Our work identifies a multistep process of nascent DNA processing at stalled replication forks in BRCA-deficient cells.

Suggested Citation

  • Ashna Dhoonmoon & Claudia M. Nicolae & George-Lucian Moldovan, 2022. "The KU-PARP14 axis differentially regulates DNA resection at stalled replication forks by MRE11 and EXO1," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32756-5
    DOI: 10.1038/s41467-022-32756-5
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    1. Anastasia Hale & Ashna Dhoonmoon & Joshua Straka & Claudia M. Nicolae & George-Lucian Moldovan, 2023. "Multi-step processing of replication stress-derived nascent strand DNA gaps by MRE11 and EXO1 nucleases," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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