Profilin-1 regulates DNA replication forks in a context-dependent fashion by interacting with SNF2H and BOD1L

Cuige Zhu, Mari Iwase, Ziqian Li, Faliang Wang, Annabel Quinet, Alessandro Vindigni and Jieya Shao ()
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Cuige Zhu: Washington University School of Medicine
Mari Iwase: Washington University School of Medicine
Ziqian Li: Washington University School of Medicine
Faliang Wang: Washington University School of Medicine
Annabel Quinet: Washington University School of Medicine
Alessandro Vindigni: Washington University School of Medicine
Jieya Shao: Washington University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract DNA replication forks are tightly controlled by a large protein network consisting of well-known core regulators and many accessory factors which remain functionally undefined. In this study, we report previously unknown nuclear functions of the actin-binding factor profilin-1 (PFN1) in DNA replication, which occur in a context-dependent fashion and require its binding to poly-L-proline (PLP)-containing proteins instead of actin. In unperturbed cells, PFN1 increases DNA replication initiation and accelerates fork progression by binding and stimulating the PLP-containing nucleosome remodeler SNF2H. Under replication stress, PFN1/SNF2H increases fork stalling and functionally collaborates with fork reversal enzymes to enable the over-resection of unprotected forks. In addition, PFN1 binds and functionally attenuates the PLP-containing fork protector BODL1 to increase the resection of a subset of stressed forks. Accordingly, raising nuclear PFN1 level decreases genome stability and cell survival during replication stress. Thus, PFN1 is a multi-functional regulator of DNA replication with exploitable anticancer potential.

Date: 2022
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DOI: 10.1038/s41467-022-34310-9

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