Evidence that the tumor-suppressor protein BRCA2 does not regulate cytokinesis in human cells

Lekomtsev, Sergey; Guizetti, Julien; Pozniakovsky, Andrei; Gerlich, Daniel W.; Petronczki, Mark

doi:10.1242/jcs.068015

Cited by 29 publications

(31 citation statements)

References 16 publications

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“…Likewise, Jonsdottir et al [55] have demonstrated that BRCA2 mutation carrier fibroblasts had delayed cytokinesis, being the mean cell division time 6 min longer compared with BRCA2 wild-type cells. However, in contrast to results from these two studies, Lekomtsev et al [56] have recently indicated that BRCA2 does not regulate cytokinesis in human cells. Thus, further research is required to verify a role of BRCA2 in the regulation of cell division.…”

Section: Discussionmentioning

confidence: 61%

Ionizing radiation or mitomycin-induced micronuclei in lymphocytes of BRCA1 or BRCA2 mutation carriers

Gutiérrez‐Enríquez

Cajal

Alonso

et al. 2010

Breast Cancer Res Treat

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BRCA1 and BRCA2 genes are essential in preserving the integrity of genome, and it is not unambiguously clear whether the heterozygosity status may affect BRCA1 or BRCA2 functions. This may have implications for the clinical management of BRCA1 and BRCA2 mutation carriers both in breast cancer (BC) screening modality and in cancer treatment based on DNA-damaging or DNA-repair-inhibiting drugs. We investigated whether lymphocytes carrying BRCA1 or BRCA2 mutations displayed an increased sensitivity to radiation or mitomycin C (MMC) in vitro treatments. Peripheral blood from 21 BRCA1 mutation carriers (12 with BC and 9 healthy), 24 BRCA2 carriers (13 with BC and 11 healthy), 15 familial BC patients without detected mutation in BRCA1 or BRCA2 and 16 controls without familial history of cancer (5 with BC and 11 healthy) were irradiated or treated with MMC. Chromosomal damage was measured using the cytokinesis-block micronucleus assay. We evaluated micronuclei (MN) and nucleoplasmic bridges (NPBs). The BRCA2 mutation carriers and familial BC patients without detected mutation in BRCA1 or BRCA2 showed less basal NPB than BRCA1 carriers and controls. The BRCA1 (+/-) or BRCA2 (+/-) lymphocytes did not have increased frequencies of MN or NPB after irradiation. In contrast, BRCA2 (+/-) lymphocytes presented higher levels of MN after MMC exposure than BRCA1 carriers and controls. The monoallelic BRCA1 or BRCA2 pathogenic mutations seem not to be associated with an enhanced radiosensitivity. The mutation of one BRCA2 allele conferred an increased sensitivity to MMC, presumably because of the role of this gene in the repair of MMC-induced DNA damage. This finding indicates that the MMC-induced MN analysis could be useful in identifying functional deficiencies of BRCA2 or genes related to BRCA2. Since MMC can be used as an anti-cancer drug, these data may be relevant for the management and follow-up of BRCA2 mutation carriers.

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Section: Discussionmentioning

confidence: 61%

Ionizing radiation or mitomycin-induced micronuclei in lymphocytes of BRCA1 or BRCA2 mutation carriers

Gutiérrez‐Enríquez

Cajal

Alonso

et al. 2010

Breast Cancer Res Treat

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“…For this, we took advantage of HeLa cells expressing BAC-encoded fulllength BRCA2, tagged with GFP and FLAG (32). Because HeLa cells carry a short telomere (Ͻ5 kb), telomerase (hTERT) was introduced into these cells to elongate the telomeres and facilitate the telomere-ChIP assay (57).…”

Section: Resultsmentioning

confidence: 99%

“…Telomere-ChIP-HeLa_CFLAP-BRCA2_hTert was generated by introducing hTert by retroviral transfer of pBabe_hTert into HeLa_CFLAP-BRCA2 cells (32). HeLa_CFLAP BRCA2_hTert cells were subjected to double thymidine block.…”

Section: Methodsmentioning

confidence: 99%

The Breast Cancer Susceptibility Gene BRCA2 Is Required for the Maintenance of Telomere Homeostasis

Min

Choi

Hwang

et al. 2012

Journal of Biological Chemistry

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Inactivating mutations in the breast cancer susceptibility gene BRCA2 cause gross chromosomal rearrangements. Chromosome structural instability in the absence of BRCA2 is thought to result from defective homology-directed DNA repair. Here, we show that BRCA2 links the fidelity of telomere maintenance with genetic integrity. Absence of BRCA2 resulted in signs of dysfunctional telomeres, such as telomere shortening, erosions, and end fusions in proliferating mouse fibroblasts. BRCA2 localized to the telomeres in S phase in an ATR-dependent manner, and its absence resulted in the accumulation of common fragile sites, particularly at the G-rich lagging strand, and increased the telomere sister chromatid exchange in unchallenged cells. The incidence of common fragile sites and telomere sister chromatid exchange increased markedly after treatment with replication inhibitors. Congruently, telomereinduced foci were frequently observed in the absence of Brca2, denoting activation of the DNA damage response and abnormal chromosome end joining. These telomere end fusions constituted a significant portion of chromosome aberrations in Brca2-deficient cells. Our results suggest that BRCA2 is required for telomere homeostasis and may be particularly important for the replication of G-rich telomeric lagging strands.The inheritance of one mutant allele of BRCA2 predisposes carriers to early onset breast cancer through loss of heterozygosity; thus, BRCA2 is a tumor suppressor (1, 2). Recently, it has been shown that BRCA2 heterozygosity also promotes Kras G12D -driven carcinogenesis (3), indicating that mutation of BRCA2 is critical for both the initiation and progression of cancer.A truncated Brca2 allele (Brca2 Tr ) in mice causes embryonic lethality and growth retardation due to accumulation of DNA double-stranded breaks (DSBs) 3 and consequent checkpoint activation (4). Metaphase chromosome spreads of the mouse embryonic fibroblasts (MEFs) from Brca2 Tr/Tr mice display chromatid, chromosome breaks, and radial structured chromosomes, strongly indicating that DSB repair is impaired in Brca2Tr/Tr mice (4). Congruently, molecular and biochemical studies of BRCA2 have revealed that BRCA2 regulates homologous recombination (HR), also called homology-directed repair (HDR) (5), by interacting with the recombinase Rad51, through the BRC repeats in exon 11 (6 -8) and the C terminus (6, 9). These studies confirmed the well defined role of BRCA2 as a tumor suppressor and a critical regulator of error-free DNA repair.HDR begins when a damaged DNA strand invades the undamaged duplex of its sister DNA strand. The damaged strand is then repaired by DNA synthesis using the sister strand as a template. Thus, HDR is an error-free DSB repair pathway that takes place during the S or G 2 phases of the cell cycle (10). Notably, HDR is implicated in the repair and rescue of stalled DNA replication forks (11). The inefficient resolution of stalled replication forks that occurs in the absence of BRCA2 greatly contributes to the accumulation of gross c...

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“…Thus, it is tempting to speculate that integrin-regulated, RSK-dependent phosphorylation of filamin A promotes cytokinesis by localizing BRCA2 to the midbody. However, we do not know whether the phosphorylation of filamin A regulates its function at the midbody; furthermore, the role of BRCA2 in cytokinesis is not universally accepted (Lekomtsev et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Integrins Promote Cytokinesis through the RSK Signaling Axis

Mathew

Nieves

Sequeira

et al. 2013

Journal of Cell Science

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Cytokinesis is the final stage in cell division. Although integrins can regulate cytokinesis, the mechanisms involved are not fully understood. In this study, we demonstrate that integrin-regulated ERK (extracellular signal-related kinase) and RSK (p90 ribosomal S6 kinase) signaling promotes successful cytokinesis. Inhibiting the activation of ERK and RSK in CHO cells by a mutation in the integrin b1 cytoplasmic tail or with pharmacological inhibitors results in the accumulation of cells with midbodies and the formation of binucleated cells. Activation of ERK and RSK signaling by the expression of constitutively active RAF1 suppresses the mutant phenotype in a RSK-dependent manner. Constitutively active RSK2 also restores cytokinesis inhibited by the mutant integrin. Importantly, the regulatory role of the RSK pathway is not specific to CHO cells. MCF-10A human mammary epithelial cells and HPNE human pancreatic ductal epithelial cells exhibit a similar dependence on RSK for successful cytokinesis. In addition, depriving mitotic MCF10A cells of integrin-mediated adhesion by incubating them in suspension suppressed ERK and RSK activation and resulted in a failure of cytokinesis. Furthermore, inhibition of RSK or integrins within the 3D context of a developing salivary gland organ explant also leads to an accumulation of epithelial cells with midbodies, suggesting a similar defect in cytokinesis. Interestingly, neither ERK nor RSK regulates cytokinesis in human fibroblasts, suggesting cell-type specificity. Taken together, our results identify the integrin-RSK signaling axis as an important regulator of cytokinesis in epithelial cells. We propose that the proper interaction of cells with their microenvironment through integrins contributes to the maintenance of genomic stability by promoting the successful completion of cytokinesis.

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Evidence that the tumor-suppressor protein BRCA2 does not regulate cytokinesis in human cells

Cited by 29 publications

References 16 publications

Ionizing radiation or mitomycin-induced micronuclei in lymphocytes of BRCA1 or BRCA2 mutation carriers

Ionizing radiation or mitomycin-induced micronuclei in lymphocytes of BRCA1 or BRCA2 mutation carriers

The Breast Cancer Susceptibility Gene BRCA2 Is Required for the Maintenance of Telomere Homeostasis

Integrins Promote Cytokinesis through the RSK Signaling Axis

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