A major function of DNA polymerases is to accurately replicate the six billion nucleotides that constitute the human genome. This task is complicated by the fact that the genome is constantly challenged by a variety of endogenous and exogenous DNA-damaging agents. DNA damage can block DNA replication or alter base coding potential, resulting in mutations. In addition, the accumulation of damage in nonreplicating DNA can affect gene expression, which leads to the malfunction of many cellular processes. A number of DNA repair systems operate in cells to remove DNA lesions, and several DNA polymerases are known to be the key components of these repair systems. In the past few years, a number of novel DNA polymerases have been discovered that likely function in replicative bypass of DNA damage missed by DNA repair enzymes or in specialized forms of repair. Furthermore, DNA polymerases can act as sensors in cell cycle checkpoint pathways that prevent entry into mitosis until damaged DNA is repaired and replication is completed. The list of DNA template-dependent eukaryotic DNA polymerases now consists of 14 enzymes with amazingly different properties. In this review, we discuss the possible functions of these polymerases in DNA damage repair, the replication of intact and damaged chromosomes, and cell cycle checkpoints.
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