Eukaryotic DNA Polymerases in Homologous Recombination

Abstract

Homologous recombination (HR) is a central process to ensure genomic stability in somatic cells and during meiosis. HR-associated DNA synthesis determines in large part the fidelity of the process. A number of recent studies have demonstrated that DNA synthesis during HR is conservative, less processive, and more mutagenic than replicative DNA synthesis. In this review, we describe mechanistic features of DNA synthesis during different types of HR-mediated DNA repair, including synthesis-dependent strand annealing, break-induced replication, and meiotic recombination. We highlight recent findings from diverse eukaryotic organisms, including humans, that suggest both replicative and translesion DNA polymerases are involved in HR-associated DNA synthesis. Our focus is to integrate the emerging literature about DNA polymerase involvement during HR with the unique aspects of these repair mechanisms, including mutagenesis and template switching.

The role of fork stalling and DNA structures in causing chromosome fragility

“…Thus, TLS polymerases may be important in replicating through mononucleotide runs or gaps formed due to bypass of secondary structures. TLS polymerases are also involved in repair of DSB breaks and could be especially important when repair through DNA structures must occur …”

Regulation of hetDNA Length during Mitotic Double-Strand Break Repair in Yeast

“…The replicative DNAP delta (Pol δ) has been implicated in HR by its ability to extend D-loops in vitro (Li et al, 2009b), and by mutations that alter gene conversion tract lengths in vivo (Giot et al, 1997; Ho et al, 2010; Maloisel et al, 2004; Maloisel et al, 2008). The precise role of Pol δ during HR, however, is unclear (reviewed by McVey et al, 2016). …”

Close encounters: Moving along bumps, breaks, and bubbles on expanded trinucleotide tracts

“…Based on structure, mammalian polymerases fall into three of five classes (Table 1), which play pivotal roles in DNA replication (pols γ, φ, ν, α, δ, ε) (family A,B), base excision repair (pol β) (family X), replication and repair in mitochondrial DNA (pol γ) (family A), non-homologous end-joining and immunological diversity (pols λ, μ, and terminaldeoxnucleotidyl transferase) (family X), and DNA damage tolerance including translesion synthesis (η, κ, ζ, Rev1) (family Y) (Table 1). Some of their known roles are summarized (Table 2), are each polymerase is described in detail in excellent reviews [70–72]. …”

“…High-fidelity polymerases have precise active site geometry and closely monitor the DNA minor groove during translocation of the nascent base pair, which can trigger the 3′–5′ exonuclease proofreading activity if a mismatch or abnormal base pair is sensed (Fig. 2A,B) [70–72,86,88,89]. However, their rigid structural constraints require correctly matched base pairs, and unusual DNA structures are not accepted in the active site [70–72,86,88–93].…”

“…2A,B) [70–72,86,88,89]. However, their rigid structural constraints require correctly matched base pairs, and unusual DNA structures are not accepted in the active site [70–72,86,88–93]. A DNA translesion polymerase (TLP) will typically lack exonuclease activity and has evolved larger active sites to accommodate the damage template, as well as the incoming nucleotide in the optimal geometry [70–72,86,88,89,91–93].…”