新核因子MARVELD1在核苷酸剪切修复通路中的调控作用及分子机制研究

Nucleotide excision repair (NER) pathway is well known to remove UV-induced photoproducts and eliminate DNA lesions. And it is the key step to recognize DNA damage sites and initiate DNA repair pathway in NER; however, the regulatory mechanism is poorly defined. Our preliminary study showed that the expression of novel nuclear factor MARVELD1 was up-regulated in response to UV irradiation, and the elevated MARVELD1 promoted the removal of UV-induced DNA lesions CPD and 6-4PP; Co-IP assay showed that MARVELD1 interacted with NER initiation factor DDB2 and H4K20me1. These data indicate that MARVELD1 is involved in recognition of DNA lesions and recruitment of repair factors in NER pathway through associating with DDB2, and regulates NER pathway via cooperating with DDB2 and H4K20me1 to induce chromatin remodeling at sites of DNA lesions. In this study, to investigate the molecular mechanism involved in the initiation step of NER pathway, we will focus on the interaction among MARVELD1, DDB2 and H4K20me1; elucidate the regulatory role of MARVELD1, as a novel component of NER pathway, in the recognition of DNA damage sites, the recruitment of repair factors and chromatin remodeling. In conclusion, we expect to disclose the regulatory mechanism by which MARVELD1 mediates the initiation step of NER pathway, and to find a new target and way for prevention and treatment of UV irradiation-associated diseases.

核苷酸剪切修复（NER）是机体细胞抵御紫外线辐射引起DNA损伤的主要途径，但目前NER通路起始的调控机制仍不清晰。申请人前期研究表明新核因子MARVELD1能够促进细胞清除紫外线辐射引起的DNA损伤产物；并发现MARVELD1与NER起始因子DDB2和单甲基化组蛋白H4K20me1相互作用，提示MARVELD1可能通过DDB2参与DNA损伤位点识别，并协同DDB2与H4K20me1对损伤DNA进行染色质重塑。本项目拟围绕MARVELD1与DDB2和H4K20me1的相互作用，深入研究MARVELD1对DNA损伤位点识别、修复因子招募和DNA损伤位点染色质重塑的调控作用，阐明MARVELD1作为NER通路的新组分在紫外线辐射引起DNA损伤修复中的分子机制，期望发现MARVELD1调控NER通路的分子机制，并为紫外线辐射损伤相关疾病的诊断和防治提供新靶点。

核苷酸剪切修复（NER）是机体细胞抵御紫外线辐射引起DNA损伤的主要途径，目前NER通路起始的调控机制仍不清晰。课题组研究中发现新核因子MARVELD1能够促进细胞清除紫外线辐射引起的DNA损伤产物；蛋白互作分析表明MARVELD1与NER起始因子DDB2和单甲基化组蛋白H4K20me1存在蛋白相互作用。机制研究中发现MARVELD1是通过DDB2参与DNA损伤位点识别，并协同DDB2与H4K20me1对损伤DNA进行染色质重塑。本课题围绕着MARVELD1与DDB2和H4K20me1的相互作用，深入研究了MARVELD1对DNA损伤位点识别、修复因子招募和DNA损伤位点染色质重塑的调控作用，阐明了MARVELD1作为NER途径的新组分在紫外线辐射引起DNA损伤修复中的分子机制，为紫外线辐射损伤相关疾病的诊断和防治提供了新靶点。