TY - JOUR
T1 - Profilin-1 regulates DNA replication forks in a context-dependent fashion by interacting with SNF2H and BOD1L
AU - Zhu, Cuige
AU - Iwase, Mari
AU - Li, Ziqian
AU - Wang, Faliang
AU - Quinet, Annabel
AU - Vindigni, Alessandro
AU - Shao, Jieya
N1 - Funding Information:
We sincerely thank Dr. Grant Stewart (University of Birmingham, UK) for sharing the BOD1L antibody, Dr. Zhongsheng You (Washington University in St. Louis, USA) for assistance with metaphase spread, and Dr. Ralph T. Bottcher and Dr. Reinhard Fassler (Max Planck Institute of Biochemistry, Germany) for providing the PFN1-null and wild type mouse chondrocytes. We thank the Alvin J. Siteman Cancer Center at Washington University for the use of the Flow Cytometry core. The Siteman Cancer Center is supported in part by an NCI Cancer Center support grant P30 CA091842. This study was partially supported by the National Cancer Institute (5R01CA181671, J.S.).
Funding Information:
The authors would like to thank the financial support received from Long Term Research Grant Scheme (LRGS/1/2018/USM/01/1/2) (UTAR4411/S01) under the Ministry of Higher Education Malaysia.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85141101743&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-34310-9
DO - 10.1038/s41467-022-34310-9
M3 - Article
C2 - 36319634
AN - SCOPUS:85141101743
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6531
ER -