Contributing Factors for Mutagenic DNA Lesion Bypass by DNA Polymerase Eta (polη)

Abstract

The integrity of DNA replication is under constant threat from various exogenous and endogenous factors along with some epigenetic factors. When there is damage to the genome, cells respond to the damage in two major ways, DNA damage repair and DNA damage tolerance. One of the major mechanisms for DNA damage tolerance is DNA lesion bypass, which is performed by specific DNA polymerases called Y-family DNA polymerases including DNA polymerase eta (polη). Ever since the discovery of polη’s unique role in bypassing cyclobutane pyrimidine dimer (CPD), a wide range of DNA lesions have been experimentally shown to be bypassed by polη. The structural study of polη was greatly boosted by the first elucidation of the N-terminal catalytic domain of polη by X-ray crystallography in 2010. Ever since, a lot of polη catalytic domain crystal structures have been published, which were complexed with an incoming nucleotide and a lesion containing DNA including pyrimidine dimers, cisplatin GpG adduct, 8-oxoguanine (oxoG), 8-oxoadenine (oxoA), N7-methylguanine (N7mG), O6-methylguanine (O6mG), hypoxanthine (HX), and many others. Though polη’s active site is known to be rigid with few conformational changes, there are several contributing factors that could facilitate the lesion bypass such as catalytic metals, syn–anti conformational equilibrium, tautomerization, and specific residues of polη. Each of these components are discussed in detail in this review.