Bypassing a 8,5′-cyclo-2′-deoxyadenosine lesion by human DNA polymerase η at atomic resolution

• DOI: 10.1073/pnas.1812856115
• Publication Date: 2018-10-01T19:07:07Z
• Authors: Peter J. Weng; Yang Gao; Mark T. Gregory; Pengcheng Wang; Yinsheng Wang; Wei Yang
• Keywords: Processivity; Thymine; Deoxyadenosine; DNA clamp; DNA polymerase II

Oxidatively induced DNA lesions 8,5′-cyclopurine-2′-deoxynucleosides (cdPus) are prevalent and cytotoxic by impeding replication transcription. Both the 5′ R - S -diastereomers of cdPu can be removed nucleotide excision repair; however, -cdPu is more resistant to repair than counterpart. Here, we report crystal structures human polymerase (Pol) η bypassing -8,5′-cyclo-2′-deoxyadenosine (cdA) in insertion following two extension steps. The cdA-containing vary response protein environment. Supported “molecular splint” Pol η, structure -cdA at 1.75-Å resolution reveals that backbone pinched toward minor groove adenine base tilted. In templating position, cdA takes up extra space usually reserved for thymine dimer, dTTP efficiently incorporated presence Mn 2+ . Rigid distortions duplex cdA, prevent normal pairing hinder immediate primer η. Our results provide structural insights into strong blockage effect mutagenic property cells.