DNA Damage, DNA Repair and Disease: Volume 2
Chapter 23: Unique Roles of Human Translesion Synthesis DNA Polymerase η
Published:11 Nov 2020
Special Collection: 2020 ebook collectionSeries: Chemical Biology
P. P. Ghodke and F. P. Guengerich, in DNA Damage, DNA Repair and Disease: Volume 2, ed. M. Dizdaroglu, R. S. Lloyd, M. Dizdaroglu, and R. S. LLoyd, The Royal Society of Chemistry, 2020, ch. 23, pp. 164-189.
Download citation file:
Human DNA polymerase η is known for faithful translesion synthesis across the cyclobutane pyrimidine dimer lesion. However, human polymerase η has roles beyond its TLS activity. Polymerase η maintains its base selectivity while incorporating rNTPs opposite 7,8-dihydro-8-oxo-dG (8-oxo-dG) and CPD lesions. Furthermore, crystallographic studies reveal that a propeller twist occurs while inserting an rNTP across 8-oxo-dG to avoid a clash between the 2′-OH group and the steric gate residue (Phe-18). Inefficient RNase H2-mediated repair was observed with two rATPs positioned opposite CPD. Polymerase η can accommodate an RNA strand as a primer as well as a template. hpol η acts as a reverse transcriptase (RT) in XP-V fibroblast and HEK293T cell extracts. The influence of an rATP and the damaged analog 1,N6-ethenoadenosine (1,N6-εrA) on TLS, RT, and RNA primer extension and RNase H2-mediated repair was also investigated. Polymerase η preferably inserts purines (dA, dG) and also generates frameshifts across from 1,N6-εrA in DNA. RNase H2 enzyme recognizes 1,N6-εrA in DNA, but exhibits partial incision activity. Furthermore, polymerase η acts as an RT in the presence of 1,N6-εrA-modified RNA. In contrast, polymerase η exhibits poor RNA primer extension activities across from 1,N6-εrA in DNA.