Maintenance of Genome Integrity: How Mammalian Cells Orchestrate Genome Duplication by Coordinating Replicative and Specialized DNA Polymerases

Abstract

Precise duplication of the human genome is challenging due to both its size and sequence complexity. DNA polymerase errors made during replication, repair or recombination are central to creating mutations that drive cancer and aging. Here, we address the regulation of human DNA polymerases, specifically how human cells orchestrate DNA polymerases in the face of stress to complete replication and maintain genome stability. DNA polymerases of the B-family are uniquely adept at accurate genome replication, but there are numerous situations in which one or more additional DNA polymerases are required to complete genome replication. Polymerases of the Y-family have been extensively studied in the bypass of DNA lesions; however, recent research has revealed that these polymerases play important roles in normal human physiology. Replication stress is widely cited as contributing to genome instability, and is caused by conditions leading to slowed or stalled DNA replication. Common Fragile Sites epitomize "difficult to replicate" genome regions that are particularly vulnerable to replication stress, and are associated with DNA breakage and structural variation. In this review, we summarize the roles of both the replicative and Y-family polymerases in human cells, and focus on how these activities are regulated during normal and perturbed genome replication.

Keywords: polymerase domains; polymerase interactions; polymerase modifications; replication stress; transcriptional regulation; translesion synthesis.

Figure 1

Overview of DNA polymerase regulation. (A) Transcriptional regulation of the B and Y-family polymerases genes (Top, see Table 1), as controlled by histone modifications (grey and orange circles), CpG methylation (open circles), and transcription factors (blue circles). Genes in red are negatively regulated by the factor below. TSS = transcription start site; (B) Post-transcriptional regulation: Polymerase mRNA stability is controlled by mRNA binding proteins and microRNA binding at the 3′ UTR; (C) Post-translational regulation: Polymerase proteins can be stabilized and functionally activated by various modifications, or prompted for degradation (red). See text for details.

Figure 2

Schematic of Y-Family Polymerase Domains and Interaction Sites. Functional domains that have been experimentally validated are indicated and drawn to scale along the length of the protein. PIP (PCNA Interacting Peptide) boxes with red highlight are putative. Below each cartoon are the known sites of interaction between the polymerase and the indicated protein. Proteins whose interaction has been suggested but the precise site is unknown are listed to the left. See text for details.

Figure 3

Orchestration of DNA Polymerases Following UV Irradiation: (A) following UV, Pol η is deubiquitinated, phosphorylated, and SUMOylated while POLI gene expression is induced; (B) thymine dimers stall replication forks requiring exchange, or altered polymerase activity (see text for details); and (C) following lesion bypass, Pol η is degraded by the proteasome while Pol κ and Pol δ (as well as Pol ε) filling in gaps generated by lesion incision by NER.