Catalytic and non-catalytic roles of DNA polymerase ? in protection of human cells against genotoxic stresses

DNA polymerase ? (Pol ?) is a specialised DNA polymerase involved in translesion DNA synthesis. Although the bypass activities across lesions are well characterised in biochemistry, its cellular protective roles against genotoxic insults are still elusive. To understand better the in vivo protective roles, the authors have established a human cell line deficient in expression of Pol ? (KO) and that expressing catalytically dead Pol ? (CD), and examined the cytotoxic sensitivity to 11 genotoxins including ultraviolet C light (UV). These cell lines were established in a genetic background of Nalm-6-MSH+, a human lymphoblastic cell line, which has high efficiency for gene targeting and functional p53 and mismatch repair activities. As a result, the authors classified the genotoxins into four groups. Group 1 includes benzo[fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][a]pyrene diolepoxide, mitomycin C and bleomycin, where the sensitivity was equally higher in KO and CD than the cell line expressing wild-type Pol ? (WT). Group 2 includes hydrogen peroxide and menadione, where the hypersensitivity was observed only in KO. Group 3 includes methyl methanesulfonate and ethyl methanesulfonate, where the hypersensitivity was observed only in CD. Group 4 includes UV and three chemicals, where the chemicals exhibited similar cytotoxicity to all three-cell lines. The results suggest that Pol ? not only protects cells from genotoxicity of DNA lesions via DNA polymerase activities but also contributes to genome integrity as a non-catalytic protein against oxidative damage caused by hydrogen peroxide and menadione. Non-catalytic roles of Pol ? in protection against oxidative damage by hydrogen peroxide are discussed.

Authors: Kanemaru Y, Suzuki T, Niimi N, Grúz P(1), Matsumoto K, Adachi N, Honma M, Nohmi T. ;Full Source: Environmental and Molecular Mutagenesis. 2015 Jun 1. doi: 10.1002/em.21961. [Epub ahead of print] ;[/fusion_builder_column][/fusion_builder_row][/fusion_builder_container]