Lin Yi-Hui, Yuan Jian, Pei Huadong, Liu Tongzheng, Ann David K, Lou Zhenkun
Department of Biochemistry and Molecular Biology, Mayo Graduate School, Rochester, Minnesota, United States of America.
Research Center for Translational Medicine, Tongji University School of Medicine, Shanghai, China; Key Laboratory of Arrhythmias of the Ministry of Education of China East Hospital, Tongji University School of Medicine, Shanghai, China.
PLoS One. 2015 Apr 23;10(4):e0123935. doi: 10.1371/journal.pone.0123935. eCollection 2015.
Homologous recombination and non-homologous end joining are two major DNA double-strand-break repair pathways. While HR-mediated repair requires a homologous sequence as the guiding template to restore the damage site precisely, NHEJ-mediated repair ligates the DNA lesion directly and increases the risk of losing nucleotides. Therefore, how a cell regulates the balance between HR and NHEJ has become an important issue for maintaining genomic integrity over time. Here we report that SIRT1-dependent KAP1 deacetylation positively regulates NHEJ. We show that up-regulation of KAP1 attenuates HR efficiency while promoting NHEJ repair. Moreover, SIRT1-mediated KAP1 deacetylation further enhances the effect of NHEJ by stabilizing its interaction with 53BP1, which leads to increased 53BP1 focus formation in response to DNA damage. Taken together, our study suggests a SIRT1-KAP1 regulatory mechanism for HR-NHEJ repair pathway choice.
同源重组和非同源末端连接是两条主要的DNA双链断裂修复途径。虽然同源重组介导的修复需要同源序列作为指导模板来精确修复损伤位点，但非同源末端连接介导的修复直接连接DNA损伤并增加了丢失核苷酸的风险。因此，细胞如何调节同源重组和非同源末端连接之间的平衡，已成为长期维持基因组完整性的一个重要问题。在此我们报告，依赖SIRT1的KAP1去乙酰化正向调节非同源末端连接。我们表明，KAP1的上调会减弱同源重组效率，同时促进非同源末端连接修复。此外，SIRT1介导的KAP1去乙酰化通过稳定其与53BP1的相互作用进一步增强非同源末端连接的效果，这导致在DNA损伤时53BP1焦点形成增加。综上所述，我们的研究提出了一种用于同源重组-非同源末端连接修复途径选择的SIRT1-KAP1调节机制。
