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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE202797 | GEO | 2022/11/15

REPOSITORIES: GEO

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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.

2022-11-15 | GSE202795 | GEO

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

2022-11-15 | GSE202796 | GEO

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

2022-11-15 | GSE202798 | GEO

Colibactin DNA damage signature indicates mutational impact in colorectal cancer

Project description:Colibactin, a potent genotoxin of Escherichia coli, causes DNA double strand breaks (DSBs). We investigated if colibactin creates a particular DNA damage signature in infected human cells. Genomic contexts of colibactin-induced DSBs were enriched for a distinct AT-rich hexameric sequence motif. A survey of somatic mutations at the colibactin target sites of several thousand cancer genomes revealed significant enrichment of the motif in colorectal cancers. Moreover, the exact break point location corresponded with mutational hot spots in these cancers corresponding to a distinct trinucleotide signature. This work provides evidence for a role of colibactin in the etiology of human cancer.

2020-04-22 | GSE145594 | GEO

DNA replication timing directly regulates the frequency of oncogenic chromosomal translocations [SNS-seq]

Project description:Many cancers originate from misregulation of gene expression caused by chromosomal translocations which result from ligation of DNA double-strand breaks (DSBs). Indeed, translocations may be causal in ~20% of human cancer morbidity 1. Although the sources of DSBs are numerous2-5, we have virtually no knowledge of the steps linking DSB formation to DSB ligation. Here, we show that early replication timing of translocation partner loci, mediated by the activity of replication origins, is a critical regulator of lymphomagenic Myc translocations generated by activation-induced deaminase (AID) during antibody maturation in B-cells. Reduced levels of the replicative helicase, the minichromosome maintenance (MCM) complex6, impairs translocation genesis, decreases firing of replication origins at AID target genes and globally abrogates the replication timing program without altering cell proliferation, gene expression or genome architecture. Strikingly, deleting a single origin of replication at Myc induces a switch from early-to-late replication at Myc with concomitantly impaired translocation frequency. This phenotype is reversed by restoring early replication at Myc thereby demonstrating a direct, causal role of replication origin activity and replication timing in translocation genesis. Finally, this replication timing-mediated step acts downstream of DSBs and is independent of DSB frequency, constituting a novel regulatory step in translocation biogenesis.

2022-09-15 | GSE161821 | GEO

DNA replication timing directly regulates the frequency of oncogenic chromosomal translocations [RNA-seq]

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DNA replication timing directly regulates the frequency of oncogenic chromosomal translocations [Repli-seq]

2022-09-15 | GSE161819 | GEO

DNA replication timing directly regulates the frequency of oncogenic chromosomal translocations [HiC]

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DNA replication timing directly regulates the frequency of oncogenic chromosomal translocations [PRO-cap]

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O-GlcNAcylation elevates topoisomerase IIα catalytic activity: a role in the chemotherapy resistance of breast cancer

Project description:DNA topoisomerase IIα (TOP2A) plays a vital role in replication and cell division by catalytically altering DNA topology. It is a prominent target for anticancer drugs. However, it is currently unknown whether TOP2A is O-GlcNAc-modified, and the mechanism by which interplay between TOP2A and O-GlcNAcylation affects breast cancer chemotherapeutic drug resistance remains unclear.

2023-03-31 | PXD041284 | iProX

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