DNA repair protein XRCC3 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''XRCC3''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
Function
This gene encodes a member of the RecA/Rad51-related protein family that participates in
homologous recombination
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in Cell (biology), cellular organi ...
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.
The XRCC3 protein is one of five
paralogs
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a speci ...
of
RAD51
DNA repair protein RAD51 homolog 1 is a protein encoded by the gene ''RAD51''. The enzyme encoded by this gene is a member of the RAD51 protein family which assists in repair of DNA double strand breaks. RAD51 family members are homologous to t ...
, including RAD51B (
RAD51L1), RAD51C (RAD51L2), RAD51D (
RAD51L3),
XRCC2 and XRCC3. They each share about 25% amino acid sequence identity with RAD51 and each other.
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.
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
DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is cons ...
.
The CX3 complex acts downstream of RAD51, after its recruitment to damage sites.
The CX3 complex associates with
Holliday junction
A Holliday junction is a branched nucleic acid structure that contains four double-stranded arms joined. These arms may adopt one of several conformations depending on buffer salt concentrations and the sequence of nucleobases closest to the j ...
resolvase activity, probably in a role of stabilizing
gene conversion
Gene conversion is the process by which one DNA sequence replaces a homologous sequence such that the sequences become identical after the conversion. Gene conversion can be either allelic, meaning that one allele of the same gene replaces another ...
tracts.
The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites.
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
RAD51 homolog C (S. cerevisiae), also known as RAD51C, is a protein which in humans is encoded by the ''RAD51C'' gene.
Function
The RAD51C protein is one of five Homology (biology)#Paralogy, paralogs of RAD51, including RAD51B (RAD51L1), RAD51 ...
.
Epigenetic deficiency in cancer
There is an
epigenetic
In biology, epigenetics is the study of changes in gene expression that happen without changes to the DNA sequence. The Greek prefix ''epi-'' (ἐπι- "over, outside of, around") in ''epigenetics'' implies features that are "on top of" or "in ...
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 recombination
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in Cell (biology), cellular organi ...
al repair.
This reduction was proposed to be a cause of breast cancer.
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.
EZH2 protein is up-regulated in numerous cancers.
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.
Interactive pathway map
See also
*
XRCC2
References
Further reading
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
{{Refend