Computational investigations on target-site searching and recognition mechanisms by thymine DNA glycosylase during DNA repair process  

作　　者：Lingyan Wang Kaiyuan Song Jin Yu Lin-Tai Da 

机构地区：[1]Key Laboratory of Systems Biomedicine(Ministry of Education),Shanghai Center for Systems Biomedicine,Shanghai Jiao Tong University,Shanghai 200240,China [2]Department of Physics and Astronomy,Department of Chemistry,NSF-Simons Center for Multiscale Cell Fate Research,University of California,Irvine,CA 92697,USA

出　　处：《Acta Biochimica et Biophysica Sinica》2022年第6期796-806,共11页生物化学与生物物理学报（英文版）

基　　金：the grants from the Natural Science Foundation of Shanghai(Nos.,20ZR1425400,21JC1403100);and the Startup Funding from Shanghai Center for Systems Biomedicine Shanghai Jiao Tong University(No.,WF220441503)。

摘　　要：DNA glycosylase, as one member of DNA repair machineries, plays an essential role in correcting mismatched/damaged DNA nucleotides by cleaving the N-glycosidic bond between the sugar and target nucleobase through the base excision repair (BER) pathways. Efficient corrections of these DNA lesions are critical for maintaining genome integrity and preventing premature aging and cancers. The target-site searching/recognition mechanisms and the subsequent conformational dynamics of DNA glycosylase, however, remain challenging to be characterized using experimental techniques. In this review, we summarize our recent studies of sequential structural changes of thymine DNA glycosylase (TDG) during the DNA repair process, achieved mostly by molecular dynamics (MD) simulations. Computational simulations allow us to reveal atomic-level structural dynamics of TDG as it approaches the target-site, and pinpoint the key structural elements responsible for regulating the translocation of TDG along DNA. Subsequently, upon locating the lesions, TDG adopts a base-flipping mechanism to extrude the mispaired nucleobase into the enzyme active-site. The constructed kinetic network model elucidates six metastable states during the base-extrusion process and suggests an active role of TDG in flipping the intrahelical nucleobase. Finally, the molecular mechanism of product release dynamics after catalysis is also summarized. Taken together, we highlight to what extent the computational simulations advance our knowledge and understanding of the molecular mechanism underlying the conformational dynamics of TDG, as well as the limitations of current theoretical work.

关 键 词：DNA repair DNA glycosylase Markov state model molecular dynamics simulation 

分 类 号：R73[医药卫生—肿瘤]