ArticleNucleic acids research2014
The human oncoprotein MDM2 induces replication stress eliciting early intra-S-phase checkpoint response and inhibition of DNA replication origin firing.
Article in Nucleic acids research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 37 citations in OpenAlex.
- Oncogenic p53 induces mitotic errors in lung cancer cells by recopying DNA replication forks conferring targetable proliferation advantage.Cell death and differentiation · 2026Article
- Mapping in silico genetic networks of the KMT2D tumour suppressor gene to uncover novel functional associations and cancer cell vulnerabilities.Genome medicine · 2024Article
- Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?Cellular & molecular biology letters · 2021Review
- MYC-Induced Replicative Stress: A Double-Edged Sword for Cancer Development and Treatment.International journal of molecular sciences · 2021Review
- Genome instability and lymphoma.Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2021Article
- Chromatin Architectural Factors as Safeguards against Excessive Supercoiling during DNA Replication.International journal of molecular sciences · 2020Review
- CEP131 Abrogates CHK1 Inhibitor-Induced Replication Defects and Is Associated with Unfavorable Outcome in Neuroblastoma.Journal of oncology · 2020Article
- Common fragile sites: protection and repair.Cell & bioscience · 2020Review
- Targeting Mouse Double Minute 2: Current Concepts in DNA Damage Repair and Therapeutic Approaches in Cancer.Frontiers in pharmacology · 2020Review
- DNA replication in progenitor cells and epithelial regeneration after lung injury requires the oncoprotein MDM2.JCI insight · 2019Article
- Inhibition of p53 inhibitors: progress, challenges and perspectives.Journal of molecular cell biology · 2019Review
- DNA replication stress: oncogenes in the spotlight.Genetics and molecular biology · 2019Article
- Chromatin modifiers Mdm2 and RNF2 prevent RNA:DNA hybrids that impair DNA replication.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Mechanisms of Oncogene-Induced Replication Stress: Jigsaw Falling into Place.Cancer discovery · 2018Review
- Estrogen-activated MDM2 disrupts mammary tissue architecture through a p53-independent pathway.Oncotarget · 2017Article
- Mutant p53 establishes targetable tumor dependency by promoting unscheduled replication.The Journal of clinical investigation · 2017Article
- MDM2 Associates with Polycomb Repressor Complex 2 and Enhances Stemness-Promoting Chromatin Modifications Independent of p53.Molecular cell · 2016Article
- Article
- Replication stress and cancer.Nature reviews. Cancer · 2015Review
- MTBP inhibits migration and metastasis of hepatocellular carcinoma.Clinical & experimental metastasis · 2015Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Conventional paradigm ascribes the cell proliferative function of the human oncoprotein mouse double minute2 (MDM2) primarily to its ability to degrade p53. Here we report that in the absence of p53, MDM2 induces replication stress eliciting an early S-phase checkpoint response to inhibit further firing of DNA replication origins. Partially synchronized lung cells cultured from p53-/-:MDM2 transgenic mice enter S phase and induce S-phase checkpoint response earlier than lung cells from p53-/- mice and inhibit firing of DNA replication origins. MDM2 activates chk1 phosphorylation, elevates mixed lineage lymphoma histone methyl transferase levels and promotes checkpoint-dependent tri-methylation of histone H3 at lysine 4, known to prevent firing of late replication origins at the early S phase. In the absence of p53, a condition that disables inhibition of cyclin A expression by MDM2, MDM2 increases expression of cyclin D2 and A and hastens S-phase entry of cells. Consistently, inhibition of cyclin-dependent kinases, known to activate DNA replication origins during firing, inhibits MDM2-mediated induction of chk1 phosphorylation indicating the requirement of this activity in MDM2-mediated chk1 phosphorylation. Our data reveal a novel pathway, defended by the intra-S-phase checkpoint, by which MDM2 induces unscheduled origin firing and accelerates S-phase entry of cells in the absence of p53.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.