Translesion DNA synthesis and mutagenesis in eukaryotes.
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ABSTRACT:
SUBMITTER: Sale JE
PROVIDER: S-EPMC3578355 | biostudies-literature | 2013 Mar
REPOSITORIES: biostudies-literature
Publications
Translesion DNA synthesis and mutagenesis in eukaryotes.
Cold Spring Harbor perspectives in biology 20130301 3
The structural features that enable replicative DNA polymerases to synthesize DNA rapidly and accurately also limit their ability to copy damaged DNA. Direct replication of DNA damage is termed translesion synthesis (TLS), a mechanism conserved from bacteria to mammals and executed by an array of specialized DNA polymerases. This chapter examines how these translesion polymerases replicate damaged DNA and how they are regulated to balance their ability to replicate DNA lesions with the risk of u ...[more]
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Project description:During very early embryogenesis of fast cleaving embryos DNA synthesis is short and surveillance mechanisms preserving genome integrity are inefficient implying the possible generation of mutations. To explore this possibility, we have analyzed mutagenesis in Xenopus laevis and Drosophila melanogaster embryos. We report the occurrence of a nucleus-to-cytoplasmic ratio-sensitive high mutation rate in Xenopus. We also show that mutagenesis is dependent upon the master regulator of translesion DNA synthesis (TLS) Rad18 and alleviated by the mismatch repair system. Unexpectedly, using separation of function mutants, we observed a homology-directed repair contribution of Rad18 in reducing the mutation load. While in Drosophila no Rad18 orthologs could be identified, genetic invalidation of TLS in the pre-blastoderm embryo resulted in reduction of both the hatching rate and Single Nucleotide Variations on specific chromosome regions in adult flies. Altogether these findings indicate that in the very early Xenopus and Drosophila embryos TLS strongly contributes to the high mutation rate. This may constitute a previously unforeseen source of genetic diversity contributing to the polymorphisms of each individual with implications for genome evolution and species adaptation.
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