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

Ashna Dhoonmoon1, Claudia M Nicolae2, George-Lucian Moldovan3

  • 1Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.

Nature Communications
|August 27, 2022
PubMed

Insights

The BRCA pathway protects genomes by suppressing DNA degradation. PARP14, a key MRE11 co-factor, prevents DNA degradation at stalled replication forks in BRCA-deficient cells, enhancing genome stability.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • The BRCA pathway is crucial for genome protection, particularly in preventing nascent DNA degradation.
  • In BRCA-deficient cells, MRE11 nuclease contributes to replication fork instability and DNA gap accumulation.

Purpose of the Study:

  • To investigate the role of PARP14 as a co-factor for MRE11 in DNA repair.
  • To elucidate the mechanism of nascent DNA processing at stalled replication forks in BRCA-deficient cells.

Main Methods:

  • Investigated the interaction and function of PARP14 with MRE11.
  • Utilized cell-based assays to assess DNA degradation, fork stability, and genome integrity.
  • Examined the role of the KU complex in protecting reversed replication forks.

Main Results:

  • PARP14 is recruited to nascent DNA during replication stress and acts as a critical co-factor for MRE11.
  • Loss or inhibition of PARP14 reduces MRE11-mediated DNA degradation and gap formation, improving genome stability and chemoresistance in BRCA-deficient cells.
  • The KU complex binds reversed forks, recruiting the PARP14-MRE11 complex to initiate controlled resection.

Conclusions:

  • PARP14 is essential for MRE11 engagement in nascent DNA processing at stalled forks in BRCA-deficient cells.
  • This PARP14-MRE11 interaction is a key step in managing replication stress and maintaining genome integrity.
  • The study reveals a multistep mechanism involving KU, PARP14, MRE11, and EXO1 in processing stalled replication forks.

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