ArticleOncogene2014
Breast cancer-associated missense mutants of the PALB2 WD40 domain, which directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair.
Article in Oncogene, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 84 papers.
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84 citing papers in PubMed, 129 citations in OpenAlex.
- A phase II study of talazoparib monotherapy in patients with wild-type BRCA1 and BRCA2 with a mutation in other homologous recombination genes.Nature cancer · 2022Trial
- A functional landscape for chromosome 17q in neuroblastoma: balancing replication stress and genomic stability.British journal of cancer · 2026Review
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- Structural analysis of genetic variants of the human tumor suppressor PALB2 coiled-coil domain.Bioscience reports · 2025Article
- The multifaceted roles of the Ctf4 replisome hub in the maintenance of genome integrity.DNA repair · 2024Review
- The human Shu complex promotes RAD51 activity by modulating RPA dynamics on ssDNA.Nature communications · 2024Article
- Genetic analysis of PALB2 gene WD40 domain in canine mammary tumour patients.Veterinary medicine and science · 2024Article
- Developments in Genetics: Better Management of Ovarian Cancer Patients.International journal of molecular sciences · 2023Review
- A genomic score to predict local control among patients with brain metastases managed with radiation.Neuro-oncology · 2023Article
- Finding significance: New perspectives in variant classification of the RAD51 regulators, BRCA2 and beyond.DNA repair · 2023Review
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- Management of PALB2-associated breast cancer: A literature review and case report.Clinical case reports · 2023Article
- PALB2 germline mutations in a large cohort of Middle Eastern breast-ovarian cancer patients.Scientific reports · 2023Article
- Arabidopsis γ-H2A.X-INTERACTING PROTEIN participates in DNA damage response and safeguards chromatin stability.Nature communications · 2022Article
- Systematic proximal mapping of the classical RAD51 paralogs unravel functionally and clinically relevant interactors for genome stability.PLoS genetics · 2022Article
- Rare germline variants in PALB2 and BRCA2 in familial and sporadic chordoma.Human mutation · 2022Article
- Functional assessment of missense variants of uncertain significance in the cancer susceptibility gene PALB2.NPJ breast cancer · 2022Article
- Characterisation of protein-truncating and missense variants inJournal of medical genetics · 2022Article
- RAD51 paralog function in replicative DNA damage and tolerance.Current opinion in genetics & development · 2021Review
24 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Heterozygous carriers of germ-line mutations in the BRCA2/FANCD1, PALB2/FANCN and RAD51C/FANCO DNA repair genes have an increased lifetime risk of developing breast, ovarian and other cancers; bi-allelic mutations in these genes clinically manifest as Fanconi anemia (FA). Here, we demonstrate that RAD51C is part of a novel protein complex that contains PALB2 and BRCA2. Further, the PALB2 WD40 domain can directly and independently bind RAD51C and BRCA2. To understand the role of these homologous recombination (HR) proteins in DNA repair, we functionally characterize effects of missense mutants of the PALB2 WD40 domain that have been reported in breast cancer patients. In contrast to large truncations of PALB2, which display a complete loss of interaction, the L939W, T1030I and L1143P missense mutants/variants of the PALB2 WD40 domain are associated with altered patterns of direct binding to the RAD51C, RAD51 and BRCA2 HR proteins in biochemical assays. Further, the T1030I missense mutant is unstable, whereas the L939W and L1143P proteins are stable but partially disrupt the PALB2-RAD51C-BRCA2 complex in cells. Functionally, the L939W and L1143P mutants display a decreased capacity for DNA double-strand break-induced HR and an increased cellular sensitivity to ionizing radiation. As further evidence for the functional importance of the HR complex, RAD51C mutants that are associated with cancer susceptibility and FA also display decreased complex formation with PALB2. Together, our results suggest that three different cancer susceptibility and FA proteins function in a DNA repair pathway based upon the PALB2 WD40 domain binding to RAD51C and BRCA2.
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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.