Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-34310-9
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Funding
- NCI Cancer Center [P30 CA091842]
- National Cancer Institute [5R01CA181671]
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This study reveals the previously unknown nuclear functions of the actin-binding factor profilin-1 (PFN1) in DNA replication. PFN1 interacts with poly-L-proline (PLP)-containing proteins to regulate DNA replication initiation, fork progression, and fork stalling under replication stress. Moreover, PFN1 collaborates with fork reversal enzymes to promote over-resection of unprotected forks. These findings suggest that PFN1 is a multi-functional regulator of DNA replication and could be potentially targeted for anti-cancer therapy.
Subcellular localization plays an important yet underappreciated role in protein functions. Here the authors defined novel and context-dependent nuclear functions of the actin-binding factor profilin-1 in DNA replication fork dynamics and stability. 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.
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