CRY2 missense mutations suppress P53 and enhance cell growth
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA695264 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13565100.fastq.gz | Fastqsanger.gz | |||
| SRR13565101.fastq.gz | Fastqsanger.gz | |||
| SRR13565102.fastq.gz | Fastqsanger.gz | |||
| SRR13565103.fastq.gz | Fastqsanger.gz | |||
| SRR13565104.fastq.gz | Fastqsanger.gz |
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Project description:Disruption of circadian rhythms increases the risk of several types of cancer. Mammalian cryptochromes (CRY1 and CRY2) are circadian transcriptional repressors that are related to DNA-repair enzymes. While CRYs lack DNA-repair activity, they modulate the transcriptional response to DNA damage, and CRY2 can promote SKP1 cullin 1-F-box (SCF)FBXL3-mediated ubiquitination of c-MYC and other targets. Here, we characterize five mutations in CRY2 observed in human cancers in The Cancer Genome Atlas. We demonstrate that two orthologous mutations of mouse CRY2 (D325H and S510L) accelerate the growth of primary mouse fibroblasts expressing high levels of c-MYC. Neither mutant affects steady-state levels of overexpressed c-MYC, and they have divergent impacts on circadian rhythms and on the ability of CRY2 to interact with SCFFBXL3 Unexpectedly, stable expression of either CRY2 D325H or of CRY2 S510L robustly suppresses P53 target-gene expression, suggesting that this may be a primary mechanism by which they influence cell growth.
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Project description:TP53, encoding for the tumor suppressor p53, is the most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, have remained enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We generated isogenic human leukemia cell lines of the most common TP53 missense mutations using CRISPR/Cas9. Functional, DNA binding, and transcriptional analyses revealed loss-of-function (LOF) without GOF effects of missense mutations. Comprehensive mutational scanning of p53 single amino acid variants demonstrated that DNA-binding domain missense variants exert dominant-negative effects (DNE). In mice, DNE of p53 missense variants confer a selective advantage on hematopoietic cells upon DNA damage in vivo. Clinical outcomes in acute myeloid leukemia patients showed no evidence of GOF for TP53 missense mutations. These findings establish dominant-negativity as the primary unit of selection for TP53 missense mutations in myeloid malignancies.
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