Abstract
X-ray Repair Cross Complementing protein 1 (XRCC1) acts as a scaffolding protein in the converging base excision repair (BER) and single strand break repair (SSBR) pathways. XRCC1 also interacts with itself and rapidly accumulates at sites of DNA damage. XRCC1 can thus mediate the assembly of large multiprotein DNA repair complexes as well as facilitate the recruitment of DNA repair proteins to sites of DNA damage. Moreover, XRCC1 is present in constitutive DNA repair complexes, some of which associate with the replication machinery. Because of the critical role of XRCC1 in DNA repair, its common variants Arg194Trp, Arg280His and Arg399Gln have been extensively studied. However, the prevalence of these variants varies strongly in different populations, and their functional influence on DNA repair and disease remains elusive. Here we present the current knowledge about the role of XRCC1 and its variants in BER and human disease/cancer.
Highlights
The exact physiological role of X-ray Repair Cross Complementing protein 1 (XRCC1) during foetal development is difficult to determine because XRCC1-deficient embryos die at around the seventh day, but the arrested embryos resemble those from AP-endonuclase 1 (APE1) deficient mice and die at approximately the same stage as DNA ligase 3 (LIG3) deficient mice embryos [3,4,5]
Xrcc1N es−cre mice are characterized by delayed growth, smaller brain size, loss of cerebellar interneurons, abnormal hippocampal function, and develop mild ataxia accompanied by episodic seizures [8]
We have found that the repertoire of proteins recruited to near-UVA (405 nm) induced DNA damage is highly dependent on the radiation dose
Summary
The human Xrcc gene is 33 kilobases long and located on chromosome 19q13.3–13.3 (Ensembl ID: ENSG00000073050). Repair activity assays indicate that N-methylpurine DNA glycosylase (MPG) binds within the aa 1 to aa 406 region of XRCC1, this was not confirmed by immunoblotting [26]. Together, these results indicate that the aa 166 to aa 403 is a central DNA glycosylase interacting region of XRCC1 (Figure 2; panels A and B). The region between the two XRCC1 BRCT domains (aa 403 to aa 538) interacts with the forkhead-associated (FHA) domains of aprataxin (APTX), polynucleotide kinase/phosphatase (PNKP), and aprataxin and PNKP like factor (APLF) (Figure 2; panels A and B) [40,41,42,43,44,45]. Interaction with XRCC1 stimulates both the phosphatase and kinase activities of recombinant PNKP [47]
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