Environmental and Molecular Mutagenesis Editor's Choice - October 2015
The Editor's Choice for October is "Catalytic and Non-Catalytic Roles of DNA Polymerase κ in the Protection of Human Cells Against Genotoxic Stresses” by Yuki Kanemaru, Tetsuyana Suzuki, Naoko Niimi, Petr Grúz, Kyomu Matsumoto, Noritaka Adachi, Masamitsu Honma, and Takehiko Nohmi.
Environmental and therapeutic carcinogens often induce mutations during the process of DNA replication and many of these mutations are generated by a class of enzymes known as translesion DNA polymerases. The replicative DNA polymerases responsible for copying the vast bulk of the genome have very high fidelity, achieved in part by a tight DNA binding domain. Damage to the DNA template may restrict access to the DNA polymerase active site thereby stalling DNA replication. Through a complex signaling pathway the stalled replicative DNA polymerase is removed from the template and replaced by a translesion DNA polymerase with a larger DNA binding pocket that can accommodate the damaged template. The translesion DNA polymerase synthesizes DNA across the damaged site sometimes without error but sometimes adding a non-complementary nucleotide across the damage. After translesion synthesis a second polymerase switch returns the replicative polymerase to the undamaged template down-stream of the damage site. When a non-complementary nucleotide is incorporated, post-replicative excision repair of the damage site will fix the mutation into both template strands. The translesion DNA polymerase that Kanemaru et al. studied, DNA polymerase kappa (polκ), is known to bypass DNA adducts produced by the chemical carcinogen, benzo[a]pyrene diolepoxide (BPDE). In this case, the translesion DNA synthesis is mostly error-free, avoiding mutations and enhancing cell survival.
Kanemaru et al. employed sophisticated molecular biology methods to generate human lymphoblastoid cell lines with targeted ablation of DNA polκ expression (KO) or with mutation of DNA polκ to generate an expressed protein without catalytic function (CD). The wildtype (WT), KO and CD lines were screened for sensitivity to a panel of DNA damaging agents. The KO and CD lines displayed the expected hypersensitivity to BPDE and another chemical that produced bulky adducts. Remarkably, the KO line, but not the CD, displayed hypersensitivity to hydrogen peroxide and menadione that oxidize DNA bases. CD cells expressing a catalytically dead DNA polκ remained resistant to oxidation. This result indicates that DNA polκ has a non-catalytic role in protection against oxidative DNA damage, an important determinant of human cancer risk. It was suggested that DNA polκ may interact physically with other translesion DNA polymerases thereby enhancing their accumulation at oxidized templates. The orchestration of replicative and translesion DNA polymerases at template damage is undoubtedly complex and a worthy subject for future investigations. Thus, the Environmental and Molecular Mutagenesis October 2015 Editor’s Choice article of “Catalytic and Non-Catalytic Roles of DNA Polymerase κ in the Protection of Human Cells Against Genotoxic Stresses” establishes two important roles that DNA polκ plays in countering chemical and physical damage to DNA. Environ. Mol. Mutagen. 56:650-662, 2015. © 2015 Wiley Periodicals, Inc.