期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2018
卷号：115
期号：42
页码：10660-10665
DOI：10.1073/pnas.1812856115
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Oxidatively induced DNA lesions 8,5′-cyclopurine-2′-deoxynucleosides (cdPus) are prevalent and cytotoxic by impeding DNA replication and transcription. Both the 5′ R - and 5′ S -diastereomers of cdPu can be removed by nucleotide excision repair; however, the 5′ S -cdPu is more resistant to repair than the 5′ R counterpart. Here, we report the crystal structures of human polymerase (Pol) η bypassing 5′ S -8,5′-cyclo-2′-deoxyadenosine (cdA) in insertion and the following two extension steps. The cdA-containing DNA structures vary in response to the protein environment. Supported by the “molecular splint” of Pol η, the structure of 5′ S -cdA at 1.75-Å resolution reveals that the backbone is pinched toward the minor groove and the adenine base is tilted. In the templating position, the cdA takes up the extra space usually reserved for the thymine dimer, and dTTP is efficiently incorporated by Pol η in the presence of Mn2+. Rigid distortions of the DNA duplex by cdA, however, prevent normal base pairing and hinder immediate primer extension by Pol η. Our results provide structural insights into the strong replication blockage effect and the mutagenic property of the cdPu lesions in cells.
关键词：context-dependent ; DNA distortion ; Mg2+ ; Mn2+ ; Ca2+
Loading...
