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Unscheduled DNA replication in G1 causes genome instability and damage signatures indicative of replication collisions

ABSTRACT: Unscheduled DNA replication in G1 causes genome instability and damage signatures indicative of replication collisions

PROVIDER: PRJNA860178 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15481000_1.fastq.gz	Fastqsanger.gz
	SRR15481000_2.fastq.gz	Fastqsanger.gz
	SRR15481100_1.fastq.gz	Fastqsanger.gz
	SRR15481100_2.fastq.gz	Fastqsanger.gz
	SRR15481001_1.fastq.gz	Fastqsanger.gz

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Unscheduled DNA replication in G1 causes genome instability and damage signatures indicative of replication collisions [mRNA-seq]

Project description:DNA replicates once per cell cycle. Interfering with the regulation of DNA replication initiation generates genome instability through over-replication and has been linked to early stages of cancer development. Here, we engineered genetic systems in budding yeast to induce unscheduled replication in the G1-phase of the cell cycle. Unscheduled G1 replication initiated at canonical S-phase origins. We quantified the composition of replisomes in G1- and S-phase and identified firing factors, polymerase alpha, and histone supply as factors that limit replication outside S-phase. G1 replication per se did not trigger cellular checkpoints. Subsequent replication during S-phase, however, resulted in over-replication and led to chromosome breaks and chromosome-wide, strand-biased occurrence of RPA-bound single-stranded DNA indicating head-to-tail replication collisions as a key mechanism generating genome instability upon G1 replication. Low-level, sporadic induction of G1 replication induced an identical response, indicating findings from synthetic systems are applicable to naturally occurring scenarios of unscheduled replication initiation.

2022-11-08 | GSE208589 | GEO

Unscheduled DNA replication in G1 causes genome instability and damage signatures indicative of replication collisions [ChIP-seq]

Project description:DNA replicates once per cell cycle. Interfering with the regulation of DNA replication initiation generates genome instability through over-replication and has been linked to early stages of cancer development. Here, we engineered genetic systems in budding yeast to induce unscheduled replication in the G1-phase of the cell cycle. Unscheduled G1 replication initiated at canonical S-phase origins across the genome. We quantified differences in replisomes in G1- and S-phase and identified firing factors, polymerase α, and histone supply as factors that limit replication outside S-phase. G1 replication per se did not trigger cellular checkpoints. Subsequent replication during S-phase, however, resulted in over-replication and led to chromosome breaks via head-to-tail replication fork collisions that are marked by chromosome-wide, strand-biased occurrence of RPA-bound single-stranded DNA. Low-level, sporadic induction of G1 replication induced an identical response, indicating findings from synthetic systems are applicable to naturally occurring scenarios of unscheduled replication initiation by G1/S deregulation.

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Unscheduled DNA replication in G1 causes genome instability and damage signatures indicative of replication collisions [ChIP-seq]

Project description:Unscheduled DNA replication in G1 causes genome instability and damage signatures indicative of replication collisions [ChIP-seq]

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Unscheduled DNA replication in G1 causes genome instability and damage signatures indicative of replication collisions [mRNA-seq]

Project description:Unscheduled DNA replication in G1 causes genome instability and damage signatures indicative of replication collisions [mRNA-seq]

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Yra1-bound R loops cause orientation-independent transcription-replication collisions and telomere instability

Project description:R loops are an important source of genome instability largely due to its negative impact on replication progression. Yra1/ALY is an abundant RNA-binding factor conserved from yeast to humans and required for mRNA export, but its excess cause lethality and genome instability. Here, we show that Yra1 binds RNA-DNA hybrids in vitro and when artificially overexpressed is recruited to chromatin in an RNA-DNA hybrid-dependent manner stabilizing R loops and converting them into replication obstacles in vivo. Importantly, excess of Yra1 increases R loop-mediated genome instability caused by transcription-replication collisions regardless of whether they are co-directional or head-on. It also induces telomere shortening and senescence, consistent with a defect in telomere replication. Our results indicate that R loops form transiently in cells regardless of replication and, after stabilization by excess Yra1, they compromise genome integrity, in agreement with a two-step model of R loop-mediated genome instability. This work opens new perspectives to understand transcription-associated genome instability in repair-deficient cells, including tumoral cells.

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RAD52 resolves replication-transcription collisions to mitigate R-loop induced genome instability

Project description:Collisions of transcription and replication machinery on the same DNA strand can pose a significant threat to genomic stability. These collision occur in part due to of RNA-DNA hybrids termed R-loops, in which a newly synthesized RNA molecule hybridizes with the DNA template strand. This study investigated the novel role of RAD52, a known DNA repair factor, in preventing collisions by managing R-loop formation and resolution. We show that RAD52 deficiency increases R-loop accumulation, exacerbating collisions and resulting in elevated DNA damage. Further, RAD52's ability to interact with the transcription machinery, coupled with its capacity to facilitate R-loop dissolution, highlights its role in preventing collisions. Lastly, we provide the first evidence of an increased mutational burden at conserved R-loop sites in human tumor samples. In summary, this study underscores the importance of RAD52 in orchestrating the delicate balance between replication and transcription processes to prevent collisions and maintain genome stability.

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Yra1-bound R loops cause orientation-independent transcription-replication collisions and telomere instability

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Unscheduled DNA replication in G1 causes genome instability and damage signatures indicative of replication collisions

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

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RNAPII-dependent ATM signaling at collisions with replication forks [DSB]

Project description:Deregulation of RNA Polymerase II (RNAPII) by oncogenic signaling leads to collisions of RNAPII with DNA synthesis machinery (transcription-replication conflicts, TRCs). TRCs can result in DNA damage and underlie genomic instability in tumor cells. Here we provide evidence that elongating RNAPII promotes activation of the ATM kinase at TRCs to drive DNA repair. We show the ATPase Wrnip1 that binds and protects stalled replication forks, associates with RNAPII and limits ATM activation. Wrnip1 binding to elongating RNAPII requires catalytic activity of the ubiquitin ligase Huwe1. Mutation of Huwe1 promotes the transfer of Wrnip1 onto replisome and induces TRCs stimulating ATM activation on RNAPII. This mechanism is evoked early upon replicative stress to induce Wrnip1 translocation and ATM signaling at TRCs. Thus, although primarily considered as genotoxic events, TRCs can provide a mechanism to maintain genome stability under replicative stress.

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