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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE202799 | GEO | 2022/11/15

REPOSITORIES: GEO

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

Project description: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.

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DNA replication initiation shapes the mutational landscape and expression of the human genome (ATAC-Seq)

Project description:The interplay between active biological processes and DNA repair is central to mutagenesis. We found 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 the formation of DNA breaks at the centre of the origins and local error-prone DNA synthesis in their immediate vicinity. To support our mutational signature analysis, we performed DSBs mapping (INDUCE-seq) in parallel with RNA-seq, ATAC-seq and TOP2A/B CUT&RUN assays and show that origin activation leads to the TOP2A/B-dependent accumulation of DSBs at origins found at TSS and splice sites of both expressed and non-expressed genes in human H9 embryonic stem cells.

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DNA replication initiation shapes the mutational landscape and expression of the human genome (RNA-Seq)

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DNA replication initiation shapes the mutational landscape and expression of the human genome (INDUCE-Seq)

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DNA replication initiation shapes the mutational landscape and expression of the human genome (CUT&RUN)

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Transcription shapes DNA replication initiation to preserve genome integrity.

Project description:BackgroundEarly DNA replication occurs within actively transcribed chromatin compartments in mammalian cells, raising the immediate question of how early DNA replication coordinates with transcription to avoid collisions and DNA damage.ResultsWe develop a high-throughput nucleoside analog incorporation sequencing assay and identify thousands of early replication initiation zones in both mouse and human cells. The identified early replication initiation zones fall in open chromatin compartments and are mutually exclusive with transcription elongation. Of note, early replication initiation zones are mainly located in non-transcribed regions adjacent to transcribed regions. Mechanistically, we find that RNA polymerase II actively redistributes the chromatin-bound mini-chromosome maintenance complex (MCM), but not the origin recognition complex (ORC), to actively restrict early DNA replication initiation outside of transcribed regions. In support of this finding, we detect apparent MCM accumulation and DNA replication initiation in transcribed regions due to anchoring of nuclease-dead Cas9 at transcribed genes, which stalls RNA polymerase II. Finally, we find that the orchestration of early DNA replication initiation by transcription efficiently prevents gross DNA damage.ConclusionRNA polymerase II redistributes MCM complexes, but not the ORC, to prevent early DNA replication from initiating within transcribed regions. This RNA polymerase II-driven MCM redistribution spatially separates transcription and early DNA replication events and avoids the transcription-replication initiation collision, thereby providing a critical regulatory mechanism to preserve genome stability.

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Rif1 regulates initiation timing of late replication origins throughout the S. cerevisiae genome

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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

Project description:DNA replication initiation shapes the mutational landscape and expression of the human genome

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Genome-wide profiles of replication initiation, single-stranded DNA accumulation, and Rad52 binding in cells exposed to replication stress

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-05-31 | GSE98462 | GEO

Sonic hedgehog accelerates DNA replication to cause replication stress promoting cancer initiation in medulloblastoma

Project description:This SuperSeries is composed of the SubSeries listed below.