Lagging-strand replication shapes the mutational landscape of the genome.

• Autores: Martin A. M. Reijns, Harriet Kemp, James Ding, Sophie Marion de Proce, Andrew P. Jackson, Martin S. Taylor
• Localización: Nature: International weekly journal of science, ISSN 0028-0836, Vol. 518, Nº 7540, 2015, págs. 502-506
• Idioma: inglés
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• Resumen

  • 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-[alpha] 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.