Loss-of-Function of xpc Sensitizes Zebrafish to Ultraviolet Irradiation

Xeroderma pigmentosum complementation group C (XPC) protein recognizes bulky DNA adducts to initiate global genomic nucleotide excision repair (GG-NER). Humans carrying germline mutations in the XPC gene display strong susceptibility to skin and certain internal cancers. In addition to its role in NER, recent studies have indicated that XPC is also involved in other DNA damage repair pathways and transcription regulation. In this report, we generated a zebrafish xpc knockout mutant. Zebrafish xpc(-/-) mutant fish develop relative normally and are fertile. However, the mutant embryos were more sensitive to ultraviolet (UV) irradiation. Upon UV irradiation, compared with the wild type embryos, mutant embryos accumulated significantly higher levels of unrepaired DNA damages and apoptotic cells, which led to more severe abnormal development. Transcriptome analysis showed that the p53 signal pathway and apoptosis were enriched in the over upregulated genes in UV-irradiated mutant embryos, suggesting that high levels of unrepaired DNA lesions activated p53 to trigger apoptotic activity in mutant embryos. More interestingly, up to 972 genes in the untreated mutant embryos were differentially expressed, compared with those in the untreated WT. Among these differentially expressed genes (DEGs), 379 genes did not respond to UV irradiation, indicating that Xpc plays a role in addition of DNA damage repair. Our results demonstrate that Xpc is an evolutionally conserved factor in NER repair. Zebrafish xpc(-/-) mutant also provides a platform to study other functions of Xpc beyond the DNA damage repair.

Automated summary

The XPC protein is involved in recognizing DNA damage and initiating nucleotide excision repair. A zebrafish xpc knockout mutant was generated and found to have increased sensitivity to UV irradiation, leading to higher levels of DNA damage and apoptosis. In addition to its role in DNA repair, XPC also plays a role in other cellular processes.