DNA双链损伤修复作为保护基因组稳定性的重要屏障，其应答过程障碍可以引起染色体结构异常进而导致肿瘤、早老症等疾病的发生。越来越多的证据表明DNA双链损伤修复是在染色质水平发生的，组蛋白修饰以及染色质重塑蛋白在这一过程中发挥着重要作用。组蛋白去甲基化酶KDM5B，与乳腺癌和前列腺癌等癌症的发生发展密切相关，但是其作用机制尚未完全阐明。我们的初步研究表明，KDM5B可以被直接招募到DNA损伤区域；其功能缺失显著的抑制了细胞DNA双链损伤修复的能力，在增强自发DNA损伤的同时增加了细胞对损伤处理的敏感性。这些结果初步提示KDM5B在DNA损伤修复以及维持基因组稳定性的过程中起着重要的作用。我们将在今后的研究中进一步探索KDM5B在这一过程中的作用以及相关分子机制。该研究将对认识以染色质为平台的损伤修复过程、如何有效的维持基因组稳定性以及肿瘤、早老症等疾病的治疗和临床药物研发提供一定的指导。

The ability of cells to maintain genome stability is critical for homeostasis, and defects in the maintenance of genome stability underlie a number of developmental disorders and human diseases including cancer and premature aging. DNA double strand breaks (DSBs) repair has been considered as a crucial barrier to keep eukarytic cell genome integrity, as DSBs and a failure to repair that damage in an appropriate manner would result in aberration of chromosome structure including translocations, deletions, inversions, and duplications. Emerging evidence suggests that DNA repair occurs in the context of highly structured chromatin and the ability of repair factors to detect DNA lesions and function properly at breaks is determined by histone modifications around the DSBs, as well as chromatin-remodelling events. Histone demethylase KDM5B has been tightly linked to the progression of breast cancer and prostate cancer. However, the role of KDM5B in tumor development and progression is not fully understood. Our preliminary data suggested that loss of function of KDM5B profoundly inhibits the efficiency of DNA DSBs repair. By combining cellular protein fractionation and Western blot analysis, we demonstrated that chromatin binding ability of KDM5B increased in response to irradiation (IR). Furthermore, chromatin immunoprecipitation (ChIP) experiment revealed that KDM5B could be directly recruited to the DSBs sites. In addition, we examined the impact of KDM5B on cellular fitness and observed that knockdown of KDM5B reduced survival ability of cells exposed to IR. Moreover, we observed that reduction of cellular levels of KDM5B is accompanied by enhenced spontaneous DNA damage, marked by H2AX phosphorylation (gammaH2AX) and p53 phosphorylation. These preliminary results indicated that KDM5B plays a role of importance in DSBs repair and maintenance of genome stability. But the underlying mechanism of how KDM5B regulate and influence on DSBs repair need to be further elucidated. We will focus on this issue in our future research. We envision that the further understanding of the molecular mechanisms through which KDM5B operates in DSBs repair, in combination with the elucidation of the physiological interactions between chromatin micro-environment and different DSBs repair pathways, will aid new approaches development to maintain genome stability and will benefit the therapeutic pursuits for many human diseases including cancer and premature aging.