Tian Li-Fei, Gao Hongwei, Yang Shuyu, Liu Yan-Ping, Li Mingzhou, Xu Wenqing, Yan Xiao-Xue
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
Int J Biol Macromol. 2023 Dec 31;253(Pt 2):126770. doi: 10.1016/j.ijbiomac.2023.126770. Epub 2023 Sep 6.
Translesion synthesis (TLS) is a kind of DNA repair that maintains the stability of the genome and ensures the normal growth of life in cells under emergencies. Y-family DNA polymerases, as a kind of error-prone DNA polymerase, mainly perform TLS. Previous studies have suggested that the occurrence of tumors is associated with the overexpression of human DNA polymerase of the Y family. And the combination of Y-family DNA polymerase inhibitors is promising for cancer therapy. Here we report the functional and structural characterization of a member of the Y-family DNA polymerases, TTEDbh. We determine TTEDbh is an extreme TLS polymerase that can cross oxidative damage sites, and further identify the amino acids and novel structures that are critical for DNA binding, synthesis, fidelity, and oxidative damage bypass. Moreover, previously unnoticed structural elements with important functions have been discovered and analyzed. These studies provide a more experimental basis for further elucidating the molecular mechanisms of DNA polymerase in the Y family. It could also shed light on the design of drugs to target tumors.
跨损伤合成（TLS）是一种DNA修复方式，可在紧急情况下维持基因组的稳定性并确保细胞中生命的正常生长。Y家族DNA聚合酶作为一种易出错的DNA聚合酶，主要执行跨损伤合成。先前的研究表明，肿瘤的发生与人类Y家族DNA聚合酶的过表达有关。并且Y家族DNA聚合酶抑制剂的联合使用在癌症治疗方面具有前景。在此，我们报告了Y家族DNA聚合酶成员TTEDbh的功能和结构特征。我们确定TTEDbh是一种极端的跨损伤合成聚合酶，能够跨越氧化损伤位点，并进一步鉴定了对DNA结合、合成、保真度和氧化损伤绕过至关重要的氨基酸和新结构。此外，还发现并分析了以前未被注意到的具有重要功能的结构元件。这些研究为进一步阐明Y家族DNA聚合酶的分子机制提供了更多实验依据。这也可能为靶向肿瘤的药物设计提供思路。
