解析DNA损伤修复的分子机制是理解衰老过程的重要基础。KAP1通过调控染色体构象的变化，在DNA损伤修复与染色体重塑过程中发挥关键作用。我们前期发现：γ射线导致双链DNA损伤，可诱发染色体重塑关键蛋白KAP1的去乙酰化，但具体机制和功能不明；进一步证据表明：KAP1是长寿基因SIRT6的底物；而KAP1去乙酰化可促进其S824、S473位点磷酸化。本项目提出“SIRT6去乙酰化KAP1，并诱导其磷酸化和染色体重塑，促进DNA损伤修复的顺利完成，从而延缓衰老过程”的假说，本项目拟采用去乙酰化、免疫荧光、MNase核酸酶DNA降解、免疫共沉淀、基因定点突变等技术，结合基因敲除与基因敲入小鼠模型研究SIRT6去乙酰化KAP1调控DNA损伤修复及染色体重塑过程的分子机制，阐明其在衰老调控中的关键作用。本项目有望深入阐明衰老发生的源动力机制，为衰老及相关疾病诊疗、防控新策略提供新思路和新靶点。

Deciphering the molecular mechanism of DNA damage repair is important for understanding the progression of aging. It has been shown that KAP1 plays a critical role in the chromatin remodeling of DNA repair process by regulating the chromatin conformation. Our preliminary data showed that γ irradiation, which causes double strand DNA break, induced the KAP1 deacetylation. However, the molecular mechanism and functional role of KAP1 deacetylation remains unclear. Further study revealed that the longevity protein SIRT6 served as the deacetylase of KAP1. The deacetylation of KAP1 promoted its phosphorylation at the sites Serine 824 and Serine 473. Herein we propose that SIRT6 deacetylates KAP1 to induce KAP1 phosphorylation and chromatin remodeling, thereby promoting DNA damage repair and slowing aging process. Multiple molecular techniques including deacetylation assay, immunofluorescence, MNase DNA digestion assay, Co-IP, gene mutagenesis, gene knout-out and gene knout-in mouse models will be applied to reveal the molecular mechanism of that SIRT6 deacetylates KAP1 to regulate chromatin remodeling and DNA damage repair, and the critical role of SIRT6-mediated KAP1 deacetylation in the regulation of aging. The results may provide further understanding of the driving mechanism of aging, and provide insights and potential targets for developing novel strategies to diagnosis, treatment and prevention of aging and related diseases.