长寿基因SIRT7调控核苷酸切除修复通路的机制研究

转录偶联核苷酸切除修复（TC-NER）通路与衰老及衰老相关疾病发生关系密切，敲除通路中重要因子可导致小鼠早衰。SIRT7是长寿蛋白Sirtuin家族成员之一，该基因敲除小鼠具有早衰表型。SIRT7已被证明参与DNA双链断裂修复并影响衰老及相关疾病发生，但SIRT7是否通过促进TC-NER延缓衰老仍有待阐明。申请人的初步研究发现SIRT7能到达UV造成的DNA损伤位点，依赖其去乙酰化酶活促进核苷酸切除修复并稳定基因组。初步机制研究发现，SIRT7与TC-NER通路中的重要蛋白CSA相互作用，且相互作用在UV处理后增强。同时SIRT7可抑制UV诱导的p21表达，提示其参与调控UV诱导的衰老发生过程。申请人计划阐明SIRT7靶向CSA调控转录偶联的核苷酸切除修复通路的机制，并模拟科凯恩氏综合征（CS）病人构建CSA突变细胞系探究SIRT7对细胞衰老的调控作用，为发展延缓衰老的新方法奠定理论基础。

Transcription-coupled nucleotide excision repair (TC-NER) pathway is closely related to the occurrence of aging and aging-related diseases. The inactivation of critical factors involved in NER, might lead to the phenotype of premature aging such as Cockayne syndrome. The longevity gene SIRT7 is a member of the Sirtuin family. Loss of SIRT7 impairs the repair of DNA double strand breaks and destabilizes genomes, possibly leading to the onset of aging or age-related diseases. However, whether SIRT7 participates in TC-NER and the potential regulatory mechanisms remain largely undetermined. Our preliminary study indicated that SIRT7 promoted the repair of UV-induced DNA damage in a deacetylase-dependent manner, thereby safeguarding genomes upon DNA damage induced by UV irradiation. Further mechanistic studies revealed that SIRT7 interacted with the TC-NER factor CSA, and the interaction was enhanced upon UV irradiation. Moreover, the applicant found that SIRT7 inhibited the UV-induced expression of p21, a critical marker of cellular senescence, indicating that SIRT7 is probably invovled in the regulation of cellular senescence through targeting NER. In this proposal, we aimed to elucidate the regulatory mechanism of SIRT7-CSA on promoting TC-NER, and examine whether SIRT7 regulates celullar senescence through targeting CSA using CS-deficiency fibroblasts. We propose that our study would lay the foundation of SIRT7 being an ideal target of delaying the onset of aging and age-associated diseases.