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

Ashna Dhoonmoon, Claudia M. Nicolae () and George-Lucian Moldovan ()
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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

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32756-5

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