The RRM domains of PARP14 mediate replication fork degradation in BRCA2-deficient cells

TL;DR

This study shows how PARP14's RRM domains help degrade DNA at stalled replication forks in cells lacking BRCA2, leading to genomic instability.

Contribution

The study identifies the role of PARP14's RRM domains in recruiting MRE11 to reversed replication forks in BRCA2-deficient cells.

Findings

PARP14's RRM domains are necessary for MRE11 recruitment to reversed replication forks in BRCA2-deficient cells.

These domains are essential for nascent strand degradation and double-strand break formation under replication stress.

The findings enhance understanding of nuclease engagement at stalled replication forks.

Abstract

Degradation of reversed replication forks by nucleases has emerged as a major mechanism of chemosensitivity in BRCA-deficient cells. We previously showed that the mono-ADP-ribosyltransferase PARP14 regulates MRE11 recruitment to reversed replication forks to promote their degradation. This results in genomic instability in BRCA-deficient cells. While it has been shown that PARP14-mediated recruitment of MRE11 to reversed forks promotes their degradation and collapse, how PARP14 binds to nascent DNA is unknown. Here, we show that, in BRCA-deficient cells, PARP14 is recruited to nascent DNA at reversed replication forks via its RRM (RNA Recognition Motifs) domains. We reveal that the RRM domains are necessary for the recruitment of MRE11 to reversed forks to promote nascent strand degradation at stalled replication forks in BRCA2-deficient cells. We also show that these domains are essential for replication stress-induced double-strand break formation in these cells. Our work furthers the understanding of nuclease recruitment and engagement at stalled forks to regulate genomic stability.

Graphical Abstract

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