ArticleMolecular and cellular biology2004
Chk2 phosphorylation of BRCA1 regulates DNA double-strand break repair.
Article in Molecular and cellular biology, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03462212 (A Randomized, Molecular Driven Phase II Trial of Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib vs Carboplatin-Paclitaxel-Rucaparib, Selected According to HRD Status, in Patients With Advanced), which is not on this map. Cited by 166 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Randomized, Molecular Driven Phase II Trial of Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib vs Carboplatin-Paclitaxel-Rucaparib, Selected According to HRD Status, in Patients With Advanced (Stage III B-C-IV) Ovarian, Primary Peritoneal and Fallopian Tube Cancer Preceded by a Phase I Dose Escalation Study on Rucaparib-Bevacizumab Combination
Who cites it
166 citing papers in PubMed, 1 synthesis or guideline pooled it, 324 citations in OpenAlex.
- Well-differentiated G1 and G2 pancreatic neuroendocrine tumors: a meta-analysis of published expanded DNA sequencing data.Frontiers in endocrinology · 2024Pooled it
- Insights into Ovarian Cancer: Unraveling the Role of DNA Double-strand Break-related Genes in Pathogenesis and Therapeutic Avenues.Reproductive sciences (Thousand Oaks, Calif.) · 2026Review
- Targeting ATR-CHK1 and ATM-CHK2 Axes in Pancreatic Cancer-A Comprehensive Review of Literature.International journal of molecular sciences · 2026Review
- Frontiers in Cell-Cycle-Targeting Therapies: Addressing the Heterogeneity of the Cancer Cell Cycle.Cancers · 2026Article
- Defining treatment-resistant brain cancer: Genetic screening to identify oncogene-driven immunomodulation and therapy resistance.Cancer gene therapy · 2026Review
- Unconventional binding of calmodulin to CHK2 kinase inhibits catalytic activity.The Biochemical journal · 2025Article
- Medicinal chemistry breakthroughs on ATM, ATR, and DNA-PK inhibitors as prospective cancer therapeutics.Journal of enzyme inhibition and medicinal chemistry · 2025Review
- ROS-ATM-CHK2 axis stabilizes HIF-1α and promotes tumor angiogenesis in hypoxic microenvironment.Oncogene · 2025Article
- Article
- Guarding against digestive-system cancers: Unveiling the role of Chk2 as a potential therapeutic target.Genes & diseases · 2025Review
- Chemo-small extracellular vesicles released in cisplatin-resistance ovarian cancer cells are regulated by the lysosomal function.Journal of extracellular biology · 2024Article
- ELK3 destabilization by speckle-type POZ protein suppresses prostate cancer progression and docetaxel resistance.Cell death & disease · 2024Article
- Antitumoral Activity of the Universal Methyl DonorMolecules (Basel, Switzerland) · 2024Article
- Clinicopathologic and genetic analysis of invasive breast carcinomas in women with germline CHEK2 variants.Breast cancer research and treatment · 2024Article
- PARP inhibitors in prostate cancers, is it time for combinations?Therapeutic advances in medical oncology · 2024Review
- Application of nitroxoline in urologic oncology - a review of evidence.Contemporary oncology (Poznan, Poland) · 2024Review
- BRCA-mutated gastric adenocarcinomas are associated with chromosomal instability and responsiveness to platinum-based chemotherapy.Journal of pathology and translational medicine · 2023Article
- Two unrelated cases with biallelic CHEK2 variants:a novel condition with constitutional chromosomal instability?European journal of human genetics : EJHG · 2023Article
- BRCA Mutations-The Achilles Heel of Breast, Ovarian and Other Epithelial Cancers.International journal of molecular sciences · 2023Review
- CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer.Nature communications · 2023Article
106 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 4 institutions in 1 country.
Funding
Abstract
The pathway determining malignant cellular transformation, which depends upon mutation of the BRCA1 tumor suppressor gene, is poorly defined. A growing body of evidence suggests that promotion of DNA double-strand break repair by homologous recombination (HR) may be the means by which BRCA1 maintains genomic stability, while a role of BRCA1 in error-prone nonhomologous recombination (NHR) processes has just begun to be elucidated. The BRCA1 protein becomes phosphorylated in response to DNA damage, but the effects of phosphorylation on recombinational repair are unknown. In this study, we tested the hypothesis that the BRCA1-mediated regulation of recombination requires the Chk2- and ATM-dependent phosphorylation sites. We studied Rad51-dependent HR and random chromosomal integration of linearized plasmid DNA, a subtype of NHR, which we demonstrate to be dependent on the Mre11-Rad50-Nbs1 complex. Prevention of Chk2-mediated phosphorylation via mutation of the serine 988 residue of BRCA1 disrupted both the BRCA1-dependent promotion of HR and the suppression of NHR. Similar results were obtained when endogenous Chk2 kinase activity was inhibited by expression of a dominant-negative Chk2 mutant. Surprisingly, the opposing regulation of HR and NHR did not require the ATM phosphorylation sites on serines 1423 and 1524. Together, these data suggest a functional link between recombination control and breast cancer predisposition in carriers of Chk2 and BRCA1 germ line mutations. We propose a dual regulatory role for BRCA1 in maintaining genome integrity, whereby BRCA1 phosphorylation status controls the selectivity of repair events dictated by HR and error-prone NHR.
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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.