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ABSTRACT: Mutational signatures reveal the role of RAD52 in p53-independent p21 driven genomic instability

PROVIDER: PRJNA431019 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6488960_1.fastq.gz	Fastqsanger.gz
	SRR6488960_2.fastq.gz	Fastqsanger.gz
	SRR6488961_1.fastq.gz	Fastqsanger.gz
	SRR6488961_2.fastq.gz	Fastqsanger.gz
	SRR6488962_1.fastq.gz	Fastqsanger.gz

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Chronic p53-independent p21 expression deregulates replication licensing, leading to genomic instability

Project description:P53 independent P21 expression deregulates replication licensing , leading to genomic instability

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Project description:The cyclin-dependent kinase inhibitor p21WAF1/Cip1 (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that, through a so-far obscure mechanism, p21 could also be oncogenic. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemo-resistance. Mechanistically, sustained p21-accumulation inhibited mainly the CRL4CDT2 ubiquitin-ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery, an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some chemotherapy drugs.

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Project description:Chronic p53-independent p21 expression deregulates replication licensing, leading to genomic instability

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Project description:Chronic p53-independent p21 expression deregulates replication licensing, leading to genomic instability II

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Project description:Chronic p53-independent p21 expression deregulates replication licensing, leading to genomic instability I

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SETD1A protects from senescence through regulation of the mitotic gene expression program

Project description:SETD1A, a member of the Set1/COMPASS family maintaining H3K4 methylation in the promoters of transcriptionally active genes, is critical for the execution of developmental gene expression and is overexpressed in multiple cancers including breast cancer1-3. Here we show that SETD1A is essential for supporting cellular mitotic processes and consequentially, its depletion leads to senescence. SETD1A directly regulates the expression of several genes orchestrating mitosis and DNA damage responses and its depletion results in multiple mitotic defects including chromosome misalignment and segregation defects. Senescence-associated cell cycle arrest in SETD1A knockdown cells is independent of the mutational status of p53, RB and p16, key mediators of this process, instead, is sustained through direct transcriptional suppression of SKP2, the ubiquitin ligase, which degrades p27 and p21. Rare cells escape senescence and re-enter the cell cycle by restoring SKP2 expression but with enhanced genomic instability. In >200 cancer cell lines and in primary circulating tumor cells, expression of SETD1A correlates with genes involved in mitosis and cell cycle suggesting a role in suppressing senescence induced by aberrant mitosis. Thus, SETD1A encodes a chromatin modifier, whose modulation may maintain the balance between senescence and genomic instability in cells.

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Project description:Collisions of the transcription and replication machineries on the same DNA strand can pose a significant threat to genomic stability. These collisions occur in part due to the formation of RNA-DNA hybrids termed R-loops, in which a newly transcribed RNA molecule hybridizes with the DNA template strand. This study investigated the role of RAD52, a known DNA repair factor, in preventing collisions by directing R-loop formation and resolution. We show that RAD52 deficiency increases R-loop accumulation, exacerbating collisions and resulting in elevated DNA damage. Furthermore, 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 evidence of an increased mutational burden from double-strand breaks at conserved R-loop sites in human tumor samples, which is increased in tumors with low RAD52 expression. In summary, this study underscores the importance of RAD52 in orchestrating the balance between replication and transcription processes to prevent collisions and maintain genome stability.

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