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Oncogenic RAS sensitizes cells to drug-induced replication stress via transcriptional silencing of P53

ABSTRACT: Oncogenic RAS sensitizes cells to drug-induced replication stress via transcriptional silencing of P53

PROVIDER: PRJNA714867 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13976856.fastq.gz	Fastqsanger.gz
	SRR13976857.fastq.gz	Fastqsanger.gz
	SRR13976858.fastq.gz	Fastqsanger.gz
	SRR13976859.fastq.gz	Fastqsanger.gz
	SRR13976860.fastq.gz	Fastqsanger.gz

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Oncogenic RAS sensitizes cells to drug-induced replication stress via transcriptional silencing of P53

Project description:Since oncogenes induce DNA replication stress (RS), cancer cells rely on the intra S-phase checkpoint for survival. Consequently, RS inducing drugs and ATR and CHK1 inhibitors are exploited as anti-cancer therapy. However, drug resistance limits efficient use. This raises the question what determines sensitivity of individual cancer cells to RS. Here, we report that oncogenic RAS dampens the P53 checkpoint which confers sensitivity to RS. We demonstrate that inducible expression of HRASG12V leads to mild RS in RPE-hTERT cells and was sufficient to sensitize cells to ATR and CHK1 inhibitors. Using RNA-sequencing we discovered that P53 signaling is essential for the response to RS. However, oncogenic RAS attenuates transcription of P53 and its target genes. Accordingly, live cell imaging shows that HRASG12V exacerbates RS in S/G2-phase. Thus, our results suggest that hyperactivation of the MAPK pathway could predict durable responses to RS inducing drugs in cancer patients

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Mouse oral tumors induced by activation of Ras and p53 mutations

Project description:The p53 gain of function p53R172H promotes accelerated tumor growth and progression to carcinoma. To identify gene expression changes associated with the oncogenic function of mutant p53 we compared the expression profiles of oral tumors induced by activation of oncogenic K-ras and p53 gain- or loss-of-function mutations Oral tumors were induced by activation of endogenous oncogenic K-rasG12D and p53 loss- or gain-of-function mutations (p53R172H) Oral tumors from mice carrying the p53R172H mutation or deletion of p53 were collected for gene expression analysis

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Altered mRNA splicing by mutant p53 activates oncogenic RAS in pancreatic cancer

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