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XRCC3-RAD51C-RAD51D-XRCC2 (XRCC3 complex) capping a RAD51 filament on single stranded DNA
Structural highlights
DiseaseRA51C_HUMAN Fanconi anemia;Hereditary breast and/or ovarian cancer syndrome. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. FunctionRA51C_HUMAN Essential for the homologous recombination (HR) pathway of DNA repair. Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA breaks arising during DNA replication or induced by DNA-damaging agents. Part of the RAD51 paralog protein complexes BCDX2 and CX3 which act at different stages of the BRCA1-BRCA2-dependent HR pathway. Upon DNA damage, BCDX2 seems to act downstream of BRCA2 recruitment and upstream of RAD51 recruitment; CX3 seems to act downstream of RAD51 recruitment; both complexes bind predominantly to the intersection of the four duplex arms of the Holliday junction (HJ) 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. The BCDX2 subcomplex RAD51B:RAD51C exhibits single-stranded DNA-dependent ATPase activity suggesting an involvement in early stages of the HR pathway. Involved in RAD51 foci formation in response to DNA damage suggesting an involvement in early stages of HR probably in the invasion step. Has an early function in DNA repair in facilitating phosphorylation of the checkpoint kinase CHEK2 and thereby transduction of the damage signal, leading to cell cycle arrest and HR activation. Participates in branch migration and HJ resolution and thus is important for processing HR intermediates late in the DNA repair process; the function may be linked to the CX3 complex. Part of a PALB2-scaffolded HR complex containing BRCA2 and which is thought to play a role in DNA repair by HR. Protects RAD51 from ubiquitin-mediated degradation that is enhanced following DNA damage. Plays a role in regulating mitochondrial DNA copy number under conditions of oxidative stress in the presence of RAD51 and XRCC3. Contributes to DNA cross-link resistance, sister chromatid cohesion and genomic stability. Involved in maintaining centrosome number in mitosis.[1] [2] [3] [4] [5] [6] [7] [8] Publication Abstract from PubMedHomologous recombination repairs DNA double strand breaks and protects stalled replication forks, but how the five RAD51 paralogs contribute to these processes remains unclear. Mutations in the RAD51 paralogs are linked to heritable breast and ovarian cancers and the cancer-prone disease Fanconi anemia. In this work, we show that the RAD51 paralogs assemble into two distinct heterotetrameric complexes, RAD51B-RAD51C-RAD51D-XRCC2 (RAD51B complex) and XRCC3-RAD51C-RAD51D-XRCC2 (XRCC3 complex). The RAD51B complex promotes dynamic adenosine triphosphate hydrolysis-dependent assembly of RAD51 filaments, whereas the XRCC3 complex stably caps the 5'-termini of RAD51 filaments to promote homologous pairing, as visualized by cryo-electron microscopy. Highly conserved across evolution, these complexes reveal insights into RAD51 filament formation and capping during DNA repair and replication fork stabilization. Cryo-electron microscopy visualization of RAD51 filament assembly and end-capping by XRCC3-RAD51C-RAD51D-XRCC2.,Greenhough LA, Galanti L, Liang CC, Boulton SJ, West SC Science. 2025 Nov 6:eaea1546. doi: 10.1126/science.aea1546. PMID:41196948[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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