Lagging-strand replication shapes the mutational landscape of the genome | |
Article | |
关键词: OKAZAKI FRAGMENT MATURATION; DNA-POLYMERASE-ALPHA; MISMATCH REPAIR; RIBONUCLEOTIDE INCORPORATION; SACCHAROMYCES-CEREVISIAE; MAMMALIAN GENOME; YEAST; FIDELITY; ERRORS; DELTA; | |
DOI : 10.1038/nature14183 | |
来源: SCIE |
【 摘 要 】
The origin of mutations is central to understanding evolution and of key relevance to health. Variation occurs non-randomly across the genome, and mechanisms for this remain to be defined. Here we report that the 5' ends of Okazaki fragments have significantly increased levels of nucleotide substitution, indicating a replicative origin for such mutations. Using a novel method, emRiboSeq, we map the genome-wide contribution of polymerases, and show that despite Okazaki fragment processing, DNA synthesized by error-prone polymerase-alpha (Pol-alpha) is retained in vivo, comprising approximately 1.5% of the mature genome. We propose that DNA-binding proteins that rapidly re-associate post-replication act as partial barriers to Pol-delta-mediated displacement of Pol-alpha-synthesized DNA, resulting in incorporation of such Pol-a tracts and increased mutation rates at specific sites. We observe a mutational cost to chromatin and regulatory protein binding, resulting in mutation hotspots at regulatory elements, with signatures of this process detectable in both yeast and humans.
【 授权许可】
Free