BDNA repair capacity

Several variants are associated with altered DNA repair capacity. Spitzet al.,111 reported that variant alleles at amino acid residues 312 and 751 of ERCC2 (XPD) were associated with reduced repair capacity in lymphocytes from individuals in a lung cancer cohort. Being homozygous for a variant allele in either XPC or XPD was associated with reduced capacity to repair UV-induced DNA damage as assayed by the host reactivation assay in a cohort of healthy subjects (Q. Wei, pers. comm.). Not surprisingly, variation in the BER gene XRCC1 was not associated with UV repair capacity. The ERCC2 751Gln variant was associated with a reduced capacity for repairing ionizing radiation using a cytogenetic-based assay112 and for removing UV-induced DNA damage.113 Hu et al.,114 report that the APE1 148Glu allele was associated with prolonged mitotic delay in lymphocytes exposed to ionizing radiation in breast cancer patients. In addition, lymphocytes from women with at least three variant alleles of APE1 and XRCC1 are at increased likelihood of exhibiting ionizing radiation sensitivity.114 At the cellular and gene specific level, the rate of repair of single strand breaks has been associated with variants of XRCC1. This reduced repair is related to the reduced ability of the variant protein to interact with Ligase 3,115 another protein of the BER pathway. Although not associated with specific variants, reduced levels of Cdk1 and Cyclin B activity have been associated with increased chromosomal breaks after radiation exposure of cells in G2,116 implicating DRC genes in this repair capacity phenotype.

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