ArticleProceedings of the National Academy of Sciences of the United States of America2017
Mutant p53 perturbs DNA replication checkpoint control through TopBP1 and Treslin.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed.
- Protein-protein interactions as therapeutic targets in breast cancer: integrated computational and experimental advances, mechanisms and clinical translation.Molecular biology reports · 2026Review
- Development of a structurally distinct TopBP1 inhibitor that enhances PARP blockade and reverses osimertinib resistance.Science advances · 2026Article
- Multi-omics analysis positions DNA2 at the interface of genome integrity programs and tumor behavior in pan-cancer.Functional & integrative genomics · 2026Article
- DNA-contact mutant p53 displaces BRCA2 from chromatin and drives R-loop-associated genome instability.Genome biology · 2026Article
- Mutant p53 Directs PARP to Regulate Replication Stress and Drive Breast Cancer Metastasis.bioRxiv : the preprint server for biology · 2026Article
- Mutant p53 variants differentially impact replication initiation and activate cGAS-STING to affect immune checkpoint inhibition.Communications biology · 2025Article
- A cancer persistent DNA repair circuit driven by MDM2, MDM4 (MDMX), and mutant p53 for recruitment of MDC1 and 53BP1 on chromatin.Nucleic acids research · 2025Article
- TOPBP1 as a potential predictive biomarker for enhanced combinatorial efficacy of olaparib and AZD6738 in PDAC.Cell & bioscience · 2025Article
- Focal adhesion kinase promotes ribosome biogenesis to drive advanced thyroid cancer cell growth and survival.Frontiers in oncology · 2025Article
- Cell hiding in colorectal cancer: correlation with response to chemotherapy in vitro and in vivo.Scientific reports · 2024Article
- From regulation to deregulation of p53 in hematologic malignancies: implications for diagnosis, prognosis and therapy.Biomarker research · 2024Review
- Mechanisms and significance of entosis for tumour growth and progression.Cell death discovery · 2024Review
- A small-molecule inhibitor of TopBP1 exerts anti-MYC activity and synergy with PARP inhibitors.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- ATF2 loss promotes 5-FU resistance in colon cancer cells via activation of the ATR-Chk1 damage response pathway.BMC cancer · 2023Article
- The C-terminus of Gain-of-Function Mutant p53 R273H Is Required for Association with PARP1 and Poly-ADP-Ribose.Molecular cancer research : MCR · 2022Article
- Gain of Function (GOF) Mutant p53 in Cancer-Current Therapeutic Approaches.International journal of molecular sciences · 2022Review
- Different hotspot p53 mutants exert distinct phenotypes and predict outcome of colorectal cancer patients.Nature communications · 2022Article
- p53 at the crossroad of DNA replication and ribosome biogenesis stress pathways.Cell death and differentiation · 2022Review
- The Chk2-PKM2 axis promotes metabolic control of vasculogenic mimicry formation in p53-mutated triple-negative breast cancer.Oncogene · 2021Article
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5 authors.
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Abstract
Accumulating evidence supports the gain-of-function of mutant forms of p53 (mutp53s). However, whether mutp53 directly perturbs the DNA replication checkpoint remains unclear. Previously, we have demonstrated that TopBP1 forms a complex with mutp53s and mediates their gain-of-function through NF-Y and p63/p73. Akt phosphorylates TopBP1 and induces its oligomerization, which inhibits its ATR-activating function. Here we show that various contact and conformational mutp53s bypass Akt to induce TopBP1 oligomerization and attenuate ATR checkpoint response during replication stress. The effect on ATR response caused by mutp53 can be exploited in a synthetic lethality strategy, as depletion of another ATR activator, DNA2, in mutp53-R273H-expressing cancer cells renders cells hypersensitive to cisplatin. Expression of mutp53-R273H also makes cancer cells more sensitive to DNA2 depletion or DNA2 inhibitors. In addition to ATR-activating function during replication stress, TopBP1 interacts with Treslin in a Cdk-dependent manner to initiate DNA replication during normal growth. We find that mutp53 also interferes with TopBP1 replication function. Several contact, but not conformational, mutp53s enhance the interaction between TopBP1 and Treslin and promote DNA replication despite the presence of a Cdk2 inhibitor. Together, these data uncover two distinct mechanisms by which mutp53 enhances DNA replication: (
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