The Xpc gene markedly affects cell survival in mouse bone marrow

Abstract

The XPC protein (encoded by the xeroderma pigmentosum Xpc gene) is a key DNA damage recognition factor that is required for global genomic nucleotide excision repair (G-NER). In contrast to transcription-coupled nucleotide excision repair (TC-NER), XPC and G-NER have been reported to contribute only modestly to cell survival after DNA damage. Previous studies were conducted using fibroblasts of human or mouse origin. Since the advent of Xpc−/− mice, no study has focused on the bone marrow of these mice. We used carboplatin to induce DNA damage in Xpc−/− and strain-matched wild-type mice. Using several independent methods, Xpc−/− bone marrow was ∼10-fold more sensitive to carboplatin than the wild type. Importantly, 12/20 Xpc−/− mice died while 0/20 wild-type mice died. We conclude that G-NER, and XPC specifically, can contribute substantially to cell survival. The data are important in the context of cancer chemotherapy, where Xpc gene status and G-NER may be determinants of response to DNA-damaging agents including carboplatin. Additionally, altered cell cycles and altered DNA damage signalling may contribute to the cell survival end point.

Genomic and functional integrity of the hematopoietic system requires tolerance of oxidative DNA lesions

“…This result suggests that unrepaired endogenous helix-distorting DNA lesions can be tolerated at the genome of proliferating cells. 6,7 Unrepaired nucleotide lesions usually arrest processive replication forks, resulting in lesion-containing single-stranded DNA (ssDNA) tracts. Persistent ssDNA tracts can collapse to cytotoxic and recombinogenic dsDNA breaks.…”

Oxidative Stress, Bone Marrow Failure, and Genome Instability in Hematopoietic Stem Cells

“…Also, fibroblasts derived from Xpc −/− mice have demonstrated OS sensitivity compared to controls by mutation accumulation and decreased survival [ 73 ]. Analysis of bone marrow cells from Xpc −/− mice shows reduced cellular viability, hypocellularity of most lineages, reduced numbers of CFU (colony-forming units), and increased sensitivity to carboplatin [ 74 ]. Since XP patients develop skin cancers by the age of 20, and the average life expectancy is early 30s, the findings in bone marrow of the Xpc −/− mice suggest the possibility that if patients were to live to later age, they could exhibit myelosuppression or bone marrow failure.…”

XPC beyond nucleotide excision repair and skin cancers

“…Moreover, colony-forming ability of Xpc-deficient BM cells was decreased 3-fold compared to wild type, even in the absence of carboplatin [90]. Comparing the results of Chen et al [40] and Fischer et al [90] it can be reasonably anticipated that XPC deficiency would result in an enhanced sensitivity to cisplatin-induced DNA damage in normal cells and can trigger the emergence of resistance when tumor cells were treated by cisplatin . [91].…”