DNA replication initiation shapes the mutational landscape and expression of the human genome.

Autor:	Murat P; Division of Protein & Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK., Perez C; Division of Protein & Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK., Crisp A; Division of Protein & Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK., van Eijk P; Broken String Biosciences Ltd., BioData Innovation Centre, Unit AB3-03, Level 3, Wellcome Genome Campus, Hinxton, Cambridge CB10 1DR, UK.; Division of Cancer & Genetics School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK., Reed SH; Broken String Biosciences Ltd., BioData Innovation Centre, Unit AB3-03, Level 3, Wellcome Genome Campus, Hinxton, Cambridge CB10 1DR, UK.; Division of Cancer & Genetics School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK., Guilbaud G; Division of Protein & Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK., Sale JE; Division of Protein & Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2022 Nov 11; Vol. 8 (45), pp. eadd3686. Date of Electronic Publication: 2022 Nov 09.
DOI:	10.1126/sciadv.add3686
Abstrakt:	The interplay between active biological processes and DNA repair is central to mutagenesis. Here, we show that the ubiquitous process of replication initiation is mutagenic, leaving a specific mutational footprint at thousands of early and efficient replication origins. The observed mutational pattern is consistent with two distinct mechanisms, reflecting the two-step process of origin activation, triggering the formation of DNA breaks at the center of origins and local error-prone DNA synthesis in their immediate vicinity. We demonstrate that these replication initiation-dependent mutational processes exert an influence on phenotypic diversity in humans that is disproportionate to the origins' genomic size: By increasing mutational loads at gene promoters and splice junctions, the presence of an origin significantly influences both gene expression and mRNA isoform usage. Last, we show that mutagenesis at origins not only drives the evolution of origin sequences but also contributes to sculpting regulatory domains of the human genome.
Databáze:	MEDLINE
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