Lagging-strand replication shapes the mutational landscape of the genome.
In: Nature, Jg. 518 (2015-02-25), Heft 7540, S. 502-506
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Zugriff:
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-α (Pol-α) 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-δ-mediated displacement of Pol-α-synthesized DNA, resulting in incorporation of such Pol-α 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. [ABSTRACT FROM AUTHOR]
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Titel: |
Lagging-strand replication shapes the mutational landscape of the genome.
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Autor/in / Beteiligte Person: | Reijns, Martin A. M. ; Kemp, Harriet ; Ding, James ; de Procé, Sophie Marion ; Jackson, Andrew P. ; Taylor, Martin S. |
Zeitschrift: | Nature, Jg. 518 (2015-02-25), Heft 7540, S. 502-506 |
Veröffentlichung: | 2015 |
Medientyp: | academicJournal |
ISSN: | 0028-0836 (print) |
DOI: | 10.1038/nature14183 |
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