Eukaryotic Translesion Polymerases and Their Roles and Regulation in DNA Damage Tolerance

Abstract

SUMMARY DNA repair and DNA damage tolerance machineries are crucial to overcome the vast array of DNA damage that a cell encounters during its lifetime. In this review, we summarize the current state of knowledge about the eukaryotic DNA damage tolerance pathway translesion synthesis (TLS), a process in which specialized DNA polymerases replicate across from DNA lesions. TLS aids in resistance to DNA damage, presumably by restarting stalled replication forks or filling in gaps that remain in the genome due to the presence of DNA lesions. One consequence of this process is the potential risk of introducing mutations. Given the role of these translesion polymerases in mutagenesis, we discuss the significant regulatory mechanisms that control the five known eukaryotic translesion polymerases: Rev1, Pol ζ, Pol κ, Pol η, and Pol ι.

Nucleolin and nucleophosmin: nucleolar proteins with multiple functions in DNA repair

“…In these cases, an alternative response, termed Translesion Synthesis (TLS), is employed in which the cell recruits one of a number of DNA polymerases (Rev1 or Pols κ, η, ζ or ι) that are specifically able to introduce a nucleotide opposite the site of DNA damage and thus replicate past the lesion, albeit at the expense of an increased rate of replicational mutagenesis arising from the more mismatch/error-permissive nature of these polymerases (Waters et al 2009). As for NER, different TLS polymerases possess specificity for different DNA lesions, with DNA Pol η being predominantly responsible for the repair of UV-induced lesions (Waters et al 2009). …”

Mouse models of DNA polymerases

“…The presence of damage tolerance pathways allows cells to temporarily bear DNA damage until the lesions are removed by DNA repair pathways. In this scenario, lesion bypass is carried out by specialized translesion synthesis (TLS) DNA polymerases [Shcherbakova and Fijalkowska, 2006;Waters et al, 2009]. As TLS polymerases lack exonuclease proofreading activity, they have reduced fidelity when replicating undamaged DNA Khare et al, 2002;Kunkel et al, 2003].…”

“…TLS polymerases can accurately bypass lesions such as bases subjected to oxidative damage, abasic sites, and bulky lesions such as nitrogen adducts [Andersen et al, 2008]. The involvement of translesion polymerases in DNA damage tolerance pathways has been extensively reviewed by Prakash et al [2005], Waters et al [2009], and Sale et al [2012]. The main TLS polymerases are the Y family polymerases Pol h, Pol j, Pol ı, Rev1, and the B family polymerase Pol f [Ohmori et al, 2009;Choi et al, 2010].…”

“…Rev1 is a deoxycytidyl transferase that inserts dCMP opposite G and certain lesions like abasic sites and guanine adducts [Nelson et al, 1996a;Waters et al, 2009]. Rev1 is proposed to act as a scaffold for multiple polymerases .…”

RAD18 polymorphisms are associated with platinum-based chemotherapy toxicity in Chinese patients with non-small cell lung cancer

“…Error-free lesion bypass switches damaged sites to undamaged DNA strands for synthesis past the DNA lesion, while errorprone lesion bypass tolerates DNA distortions to allow synthesis past the lesion [13] . Instead of cutting the mutation base or nucleotide around the lesions and making another copy of the opposite template, the TLS pathway permits continuity of the replication fork by allowing replication through these lesions [14] . First, one of the translesion synthesis polymerases is recruited to the stalled replication fork for replication over the lesion, which is facilitated by DNA damage-induced PCNA monoubiquitination [15,16] .…”