ArticleProceedings of the National Academy of Sciences of the United States of America2016
CHK2-BRCA1 tumor-suppressor axis restrains oncogenic Aurora-A kinase to ensure proper mitotic microtubule assembly.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 64 citations in OpenAlex.
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- Docetaxel response in BRCA1,p53-deficient mammary tumor cells is affected by Huntingtin and BAP1.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- The significant others of aurora kinase a in cancer: combination is the key.Biomarker research · 2024Review
- BRCA1 orchestrates the response to BI-2536 and its combination with alisertib in MYC-driven small cell lung cancer.Cell death & disease · 2024Article
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- Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival.Research square · 2023Article
- BRCA1 transports the DNA damage signal for CDDP-induced centrosome amplification through the centrosomal Aurora A.Cancer science · 2022Article
- Molecular Management of High-Grade Serous Ovarian Carcinoma.International journal of molecular sciences · 2022Review
- Regulation of BRCA1 stability through the tandem UBX domains of isoleucyl-tRNA synthetase 1.Nature communications · 2022Article
- MKLP2 functions in early mitosis to ensure proper chromosome congression.Journal of cell science · 2022Article
- Mitotic protein kinase-driven crosstalk of machineries for mitosis and metastasis.Experimental & molecular medicine · 2022Review
- GSTpi reduces DNA damage and cell death by regulating the ubiquitination and nuclear translocation of NBS1.Cellular and molecular life sciences : CMLS · 2021Article
- Mutations in Profilin 1 Cause Early-Onset Paget's Disease of Bone With Giant Cell Tumors.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2021Article
- Competition between two phosphatases fine-tunes Hedgehog signaling.The Journal of cell biology · 2021Article
- Mitotic and DNA Damage Response Proteins: Maintaining the Genome Stability and Working for the Common Good.Frontiers in cell and developmental biology · 2021Review
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
BRCA1 (breast cancer type 1 susceptibility protein) is a multifunctional tumor suppressor involved in DNA damage response, DNA repair, chromatin regulation, and mitotic chromosome segregation. Although the nuclear functions of BRCA1 have been investigated in detail, its role during mitosis is little understood. It is clear, however, that loss of BRCA1 in human cancer cells leads to chromosomal instability (CIN), which is defined as a perpetual gain or loss of whole chromosomes during mitosis. Moreover, our recent work has revealed that the mitotic function of BRCA1 depends on its phosphorylation by the tumor-suppressor kinase Chk2 (checkpoint kinase 2) and that this regulation is required to ensure normal microtubule plus end assembly rates within mitotic spindles. Intriguingly, loss of the positive regulation of BRCA1 leads to increased oncogenic Aurora-A activity, which acts as a mediator for abnormal mitotic microtubule assembly resulting in chromosome missegregation and CIN. However, how the CHK2-BRCA1 tumor suppressor axis restrains oncogenic Aurora-A during mitosis to ensure karyotype stability remained an open question. Here we uncover a dual molecular mechanism by which the CHK2-BRCA1 axis restrains oncogenic Aurora-A activity during mitosis and identify BRCA1 itself as a target for Aurora-A relevant for CIN. In fact, Chk2-mediated phosphorylation of BRCA1 is required to recruit the PP6C-SAPS3 phosphatase, which acts as a T-loop phosphatase inhibiting Aurora-A bound to BRCA1. Consequently, loss of CHK2 or PP6C-SAPS3 promotes Aurora-A activity associated with BRCA1 in mitosis. Aurora-A, in turn, then phosphorylates BRCA1 itself, thereby inhibiting the mitotic function of BRCA1 and promoting mitotic microtubule assembly, chromosome missegregation, and CIN.
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