RAD51C-XRCC3 structure and cancer patient mutations define DNA replication roles.

Autor: Longo MA; Department of Molecular & Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX, USA., Roy S; Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, TX, USA., Chen Y; Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, TX, USA., Tomaszowski KH; Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, TX, USA., Arvai AS; The Department of Integrative Structural & Computational Biology, The Scripps Research Institute, La Jolla, CA, USA., Pepper JT; Department of Biochemistry and Molecular Biology, Robson DNA Science Centre, Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada., Boisvert RA; Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, TX, USA., Kunnimalaiyaan S; Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, TX, USA., Keshvani C; Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, TX, USA., Schild D; Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA., Bacolla A; Department of Molecular & Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX, USA., Williams GJ; Department of Biochemistry and Molecular Biology, Robson DNA Science Centre, Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. gareth.williams2@ucalgary.ca., Tainer JA; Department of Molecular & Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX, USA. jtainer@mdanderson.org.; Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, TX, USA. jtainer@mdanderson.org., Schlacher K; Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, TX, USA. kschlacher@mdanderson.org.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Jul 24; Vol. 14 (1), pp. 4445. Date of Electronic Publication: 2023 Jul 24.
DOI: 10.1038/s41467-023-40096-1
Abstrakt: RAD51C is an enigmatic predisposition gene for breast, ovarian, and prostate cancer. Currently, missing structural and related functional understanding limits patient mutation interpretation to homology-directed repair (HDR) function analysis. Here we report the RAD51C-XRCC3 (CX3) X-ray co-crystal structure with bound ATP analog and define separable RAD51C replication stability roles informed by its three-dimensional structure, assembly, and unappreciated polymerization motif. Mapping of cancer patient mutations as a functional guide confirms ATP-binding matching RAD51 recombinase, yet highlights distinct CX3 interfaces. Analyses of CRISPR/Cas9-edited human cells with RAD51C mutations combined with single-molecule, single-cell and biophysics measurements uncover discrete CX3 regions for DNA replication fork protection, restart and reversal, accomplished by separable functions in DNA binding and implied 5' RAD51 filament capping. Collective findings establish CX3 as a cancer-relevant replication stress response complex, show how HDR-proficient variants could contribute to tumor development, and identify regions to aid functional testing and classification of cancer mutations.
(© 2023. The Author(s).)
Databáze: MEDLINE
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