The putative oncogene CEP72 inhibits the mitotic function of BRCA1 and induces chromosomal instability

Lüddecke, Sina; Ertych, Norman; Stenzinger, Albrecht; Weichert, Wilko; Beißbarth, T; Dyczkowski, Jerzy; Gaedcke, Jochen; Valerius, Oliver; Braus, Gerhard H.; Kschischo, Maik; Bastians, Holger

doi:10.1038/onc.2015.290

Cited by 24 publications

(30 citation statements)

References 27 publications

(39 reference statements)

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“…Importantly, among the proteins that showed reduced interaction with BRCA1 upon loss of CHK2 [heavy/light (H/L) ratio >2], we found SAPS3, also known as PPP6R3 (H/L ratio = 2.7; Dataset S1: GI: 88941982). SAPS3 (GI: 194382030) also was identified in our previous mass spectrometry analyses (14) as a BRCA1-interacting protein. This protein immediately caught our attention, because SAPS3 represents a regulatory subunit of PP6 (12), which recently has been identified as a T-loop phosphatase for Aurora-A (11).…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, Aurora-A can act as a negative regulator of BRCA1 in mitosis, and, as such, AURKA represents a well-established oncogene that is overexpressed in various human malignancies and is clearly associated with chromosome missegregation and CIN (6,9,10). In addition, recent work from our laboratories has identified the centrosomal protein Cep72 as a putative oncogene in colorectal cancer that can bind to BRCA directly and inhibits its mitotic function to regulate microtubule growth (14). In sum, our work not only reveals a key regulatory circuit on BRCA1 but also provides a network of cancer-associated genetic lesions that might contribute to the functional inactivation of BRCA1 during mitosis.…”

Section: Discussionmentioning

confidence: 99%

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CHK2 – BRCA1 tumor-suppressor axis restrains oncogenic Aurora-A kinase to ensure proper mitotic microtubule assembly

Ertych

Stolz

Valerius

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CHK2 – BRCA1 tumor-suppressor axis restrains oncogenic Aurora-A kinase to ensure proper mitotic microtubule assembly

Ertych

Stolz

Valerius

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Brca1, when recruited to centrosome, interacts with a plethora of centrosomal proteins like γ-tubulin [ 51 ], Nlp [ 50 ], OLA1 [ 49 ], and KIAA0101 [ 101 ], ensuring error-free centrosomal duplication and cytokinesis. Most importantly, a recent finding demonstrates binding of a Cep family protein (Cep72) to Brca1, thus disturbing centrosomal regulation by Brca1 and consequently triggering genomic instability [ 102 ]. According to a recent report, Brca2 functions with Cep55 to regulate cytokinesis and ploidy [ 103 ].…”

Section: Discussionmentioning

confidence: 99%

Noncoding RNA Ginir functions as an oncogene by associating with centrosomal proteins

et al. 2018

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Long noncoding RNAs constitute a major fraction of the eukaryotic transcriptome, and together with proteins, they intricately fine-tune various growth regulatory signals to control cellular homeostasis. Here, we describe the functional characterisation of a novel pair of long intergenic noncoding RNAs (lincRNAs) comprised of complementary, fully overlapping sense and antisense transcripts Genomic Instability Inducing RNA (Ginir) and antisense RNA of Ginir (Giniras), respectively, from mouse cells. This transcript pair is expressed in a spatiotemporal manner during embryonic development. The individual levels of the sense and antisense transcripts are finely balanced during embryonic growth and in adult tissues. Functional studies of the individual transcripts performed using overexpression and knock-down strategies in mouse cells has led to the discovery that Ginir RNA is a regulator of cellular proliferation and can act as an oncogene having a preeminent role in malignant transformation. Mechanistically, we demonstrate that the oncogenic function of Ginir is mediated by its interaction with centrosomal protein 112 (Cep112). Additionally, we establish here a specific interaction between Cep112 with breast cancer type 1 susceptibility protein (Brca1), another centrosome-associated protein. Next, we prove that the mutual interaction between Cep112 with Brca1 is significant for mitotic regulation and maintenance of genomic stability. Furthermore, we demonstrate that the Cep112 protein interaction with Brca1 protein is impaired when an elevated level of Ginir RNA is present in the cells, resulting in severe deregulation and abnormality in mitosis, leading to malignant transformation. Inhibiting the Ginir RNA function in transformed cells attenuates transformation and restores genomic stability. Together, these findings unravel, to our knowledge, a hitherto-unknown mechanism of oncogenesis mediated by a long noncoding RNA and establishes a unique role of Cep112–Brca1 interaction being modulated by Ginir RNA in maintaining mitotic fidelity.

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“…Elevated microtubule (MT) dynamics leading to delayed chromosome congression, chromosome segregation errors and CIN was recently described in colorectal cancer as a result of either Aurora A overexpression 9 or the deregulation of the Chk2-BRCA1 axis 10,41 .…”

Section: Supernumerary Centrosomes and Aberrant Mt Dynamics Contributmentioning

confidence: 99%

Mechanisms of Chromosomal Instability in High-grade Serous Ovarian Carcinoma

Tamura

Shaikh

Muliaditan

et al. 2019

Preprint

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Chromosomal instability (CIN), the continual gain and loss of chromosomes or parts of chromosomes, occurs in the majority of cancers and confers poor prognosis. Mechanisms driving CIN remain unknown in most cancer types due to a scarcity of functional studies.High-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, is the major cause of death due to gynaecological malignancy in the Western world with chemotherapy resistance developing in almost all patients. HGSC exhibits high rates of chromosome aberrations and knowledge of causative mechanisms is likely to represent an important step towards combating the poor prognosis of this disease. However, very little is known about the nature of chromosomal instability exhibited by this cancer type in particular due to a historical lack of appropriate cell line models. Here we perform the first in-depth functional characterisation of mechanisms driving CIN in HGSC by analysing eight cell lines that accurately recapitulate HGSC genetics as defined by recent studies. We show, using a range of established functional CIN assays combined with live cell imaging and single molecule DNA fibre analysis, that multiple mechanisms co-exist to drive CIN in HGSC.These include supernumerary centrosomes, elevated microtubule dynamics and DNA replication stress. By contrast, the spindle assembly checkpoint was intact. These findings are relevant for developing therapeutic approaches to manipulating CIN in ovarian cancer, and suggests that such approaches may need to be multimodal to combat multiple co-existing CIN drivers.

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The putative oncogene CEP72 inhibits the mitotic function of BRCA1 and induces chromosomal instability

Cited by 24 publications

References 27 publications

CHK2 – BRCA1 tumor-suppressor axis restrains oncogenic Aurora-A kinase to ensure proper mitotic microtubule assembly

CHK2 – BRCA1 tumor-suppressor axis restrains oncogenic Aurora-A kinase to ensure proper mitotic microtubule assembly

Noncoding RNA Ginir functions as an oncogene by associating with centrosomal proteins

Mechanisms of Chromosomal Instability in High-grade Serous Ovarian Carcinoma

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