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

Ashna Dhoonmoon, Claudia M Nicolae, George-Lucian Moldovan

Nature communications 2022 Aug 27

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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. © 2022. The Author(s).

Citation

Ashna Dhoonmoon, Claudia M Nicolae, George-Lucian Moldovan. The KU-PARP14 axis differentially regulates DNA resection at stalled replication forks by MRE11 and EXO1. Nature communications. 2022 Aug 27;13(1):5063