DNA repair protein XRCC3 is a protein that in humans is encoded by the XRCC3 gene.[5]
Function
This gene encodes a member of the RecA/Rad51-related protein family that participates in homologous recombination to maintain chromosome stability and repair DNA damage. This gene functionally complements Chinese hamster irs1SF, a repair-deficient mutant that exhibits hypersensitivity to a number of different DNA-damaging agents and is chromosomally unstable. A rare microsatellite polymorphism in this gene is associated with cancer in patients of varying radiosensitivity.[6]
The XRCC3 protein is one of five paralogs of RAD51, including RAD51B (RAD51L1), RAD51C (RAD51L2), RAD51D (RAD51L3), XRCC2 and XRCC3. They each share about 25% amino acid sequence identity with RAD51 and each other.[7]
The RAD51 paralogs are all required for efficient DNA double-strand break repair by homologous recombination and depletion of any paralog results in significant decreases in homologous recombination frequency.[8]
Two paralogs form a complex designated CX3 (RAD51C-XRCC3). Four paralogs form a second complex designated BCDX2 (RAD51B-RAD51C-RAD51D-XRCC2). These two complexes act at two different stages of homologous recombinational DNA repair.
The CX3 complex acts downstream of RAD51, after its recruitment to damage sites.[8] The CX3 complex associates with Holliday junction resolvase activity, probably in a role of stabilizing gene conversion tracts.[8]
The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites.[8] The BCDX2 complex appears to act by facilitating the assembly or stability of the RAD51 nucleoprotein filament.
Interactions
XRCC3 has been shown to interact with RAD51C.[9][10][11][12]
Epigenetic deficiency in cancer
There is an epigenetic cause of XRCC3 deficiency that appears to increase cancer risk. This is the repression of XRCC3 by over-expression of EZH2 protein.
Increased expression of EZH2 leads to epigenetic repression of RAD51 paralogs, including XRCC3, and thus reduces homologous recombinational repair.[13] This reduction was proposed to be a cause of breast cancer.[13] EZH2 is the catalytic subunit of Polycomb Repressor Complex 2 (PRC2) which catalyzes methylation of histone H3 at lysine 27 (H3K27me) and mediates gene silencing of target genes via local chromatin reorganization.[14] EZH2 protein is up-regulated in numerous cancers.[14][15] EZH2 mRNA is up-regulated, on average, 7.5-fold in breast cancer, and between 40% and 75% of breast cancers have over-expressed EZH2 protein.[16]
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
