8gbj
From Proteopedia
Cryo-EM structure of a human BCDX2/ssDNA complex
Structural highlights
DiseaseRA51D_HUMAN Hereditary breast and/or ovarian cancer syndrome;Familial prostate cancer. Disease susceptibility is associated with variants affecting the gene represented in this entry. FunctionRA51D_HUMAN Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA breaks arising during DNA replication or induced by DNA-damaging agents. Bind to single-stranded DNA (ssDNA) and has DNA-dependent ATPase activity. Part of the RAD51 paralog protein complex BCDX2 which acts in the BRCA1-BRCA2-dependent HR pathway. Upon DNA damage, BCDX2 acts downstream of BRCA2 recruitment and upstream of RAD51 recruitment. BCDX2 binds predominantly to the intersection of the four duplex arms of the Holliday junction and to junction of replication forks. The BCDX2 complex was originally reported to bind single-stranded DNA, single-stranded gaps in duplex DNA and specifically to nicks in duplex DNA. Involved in telomere maintenance. The BCDX2 subcomplex XRCC2:RAD51D can stimulate Holliday junction resolution by BLM.[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedHomologous recombination (HR) fulfils a pivotal role in the repair of DNA double-strand breaks and collapsed replication forks(1). HR depends on the products of several paralogues of RAD51, including the tetrameric complex of RAD51B, RAD51C, RAD51D and XRCC2 (BCDX2)(2). BCDX2 functions as a mediator of nucleoprotein filament assembly by RAD51 and single-stranded DNA (ssDNA) during HR, but its mechanism remains undefined. Here we report cryogenic electron microscopy reconstructions of human BCDX2 in apo and ssDNA-bound states. The structures reveal how the amino-terminal domains of RAD51B, RAD51C and RAD51D participate in inter-subunit interactions that underpin complex formation and ssDNA-binding specificity. Single-molecule DNA curtain analysis yields insights into how BCDX2 enhances RAD51-ssDNA nucleoprotein filament assembly. Moreover, our cryogenic electron microscopy and functional analyses explain how RAD51C alterations found in patients with cancer(3-6) inactivate DNA binding and the HR mediator activity of BCDX2. Our findings shed light on the role of BCDX2 in HR and provide a foundation for understanding how pathogenic alterations in BCDX2 impact genome repair. Structural insights into BCDX2 complex function in homologous recombination.,Rawal Y, Jia L, Meir A, Zhou S, Kaur H, Ruben EA, Kwon Y, Bernstein KA, Jasin M, Taylor AB, Burma S, Hromas R, Mazin AV, Zhao W, Zhou D, Wasmuth EV, Greene EC, Sung P, Olsen SK Nature. 2023 Jul;619(7970):640-649. doi: 10.1038/s41586-023-06219-w. Epub 2023 , Jun 21. PMID:37344589[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
Categories: Homo sapiens | Large Structures | Synthetic construct | Greene EC | Jia L | Meir A | Olsen SK | Rawal Y | Ruben EA | Sung P | Wasmuth EV
