Inactivation of the Nijmegen Breakage Syndrome Gene Leads to Excess Centrosome Duplication via the ATR/BRCA1 Pathway

Shimada, Morimi; Sagae, Ruri; Kobayashi, Junya; Habu, Toshiyuki; Komatsu, Kenshi

doi:10.1158/0008-5472.can-08-3016

Cited by 29 publications

(36 citation statements)

References 47 publications

(65 reference statements)

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confidence: 99%

“…(12) Given that downregulation of the NBS1 protein reduces the ubiquitination of c-tubulin, NBS1 could be involved in the maintenance of the proper number of centrosomes through BRCA1-mediated ubiquitination of c-tubulin. (12) Other DNA repair proteins, such as the DNA-dependent protein kinase catalytic subunit (DNAPKcs), also localize at the centrosome; however, their function at the centrosome is not clear. (13) Ionizing radiation (IR) induces DNA double-strand breaks (DSBs), a potentially lethal type of DNA damage, and generates chromosome aberrations and gene mutations, and leads to apoptosis.…”

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Differential role of repair proteins, BRCA1/NBS1 and Ku70/DNA‐PKcs, in radiation‐induced centrosome overduplication

Shimada

Kobayashi

Hirayama³

et al. 2010

Cancer Science

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Centrosomes are important cytoplasmic organelles involved in chromosome segregation, defects in which can result in aneuploidy, and contribute to tumorigenesis. It is known that DNA damage causes the supernumerary centrosomes by a mechanism in which centrosomes continue to duplicate during cell cycle arrest at checkpoints. We show here that ionizing radiation induces the overduplication of centrosomes in a dose-dependent manner, and that the level of overduplication is pronounced in BRCA1-and NBS1-deficient cells, even though their checkpoint control is abrogated. Conversely, marginal increases in overduplication were observed in Ku70-and DNA-PKcs-deficient cells, which are intact in checkpoint control. The frequency of radiation-induced overduplication of centrosomes might be associated with DNA repair, as it was decreased with reduced cell killing after protracted exposures to radiation. As a result, when the frequency of radiation-induced centrosome overduplication was plotted against radiation-induced cell killing, similar curves were seen for both protracted and acute exposures in wild-type cells, Ku70-deficient, and DNA-PKcs-deficient cells, indicating a common mechanism for centrosome overduplication. However, the absence of either BRCA1 or NBS1 enhanced radiation-induced overduplication frequencies by 2-4-fold on the basis of the same cell killing. These results suggest that radiation-induced centrosome overduplication is regulated by at least two mechanisms: a checkpoint-dependent pathway involved in wild-type cells, Ku70-deficient and DNA-PKcs-deficient cells; and a checkpoint-independent pathway as observed in BRCA1-deficient and NBS1-deficient cells. (Cancer Sci 2010; 101: 2531-2537 T he centrosome, an organelle consisting of a pair of centrioles surrounded by pericentriolar material, is necessary for proper chromosome segregation during cell division.(1,2) Centrosomes duplicate only once during each cell division cycle. When the proper number of centrosomes is not present, the formation of multiple mitotic spindles and aneuploidy can occur, leading to tumorigenesis.(3,4) BRCA1, an ovarian and breast cancer-specific tumor suppressor protein, (5)(6)(7) localize at the centrosomes, and suppression of BRCA1 leads to centrosome overduplication.(8) BRCA1 is an E3 ubiquitin ligase that ubiquitinates c-tubulin, a key protein for the formation of pericentriolar material.(5) Defects in the ubiquitination activity of BRCA1 lead to centrosome overduplication and abnormal aster formation, (9,10) suggesting that the ubiquitination is required to maintain the proper number of centrosomes in cells. Hypomorphic mutations in the NBS1 protein result in Nijmegen breakage syndrome (NBS), which is characterized by a predisposition towards malignancies.(11) NBS1 localizes at the centrosomes by forming complexes with BRCA1; the knockdown of NBS1 in mammalian cells results in centrosome overduplication. (12) Given that downregulation of the NBS1 protein reduces the ubiquitination of c-tubulin, NBS1 could be involved in the ...

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confidence: 99%

Differential role of repair proteins, BRCA1/NBS1 and Ku70/DNA‐PKcs, in radiation‐induced centrosome overduplication

Shimada

Kobayashi

Hirayama³

et al. 2010

Cancer Science

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“…MDC1 can interact with ATM, and this interaction induces the accumulation of ATM at DSB sites, which amplifies and distributes γ-H2AX around DSB sites (Lou et al, 2006). H2AX-deficient cells show defects in HR repair and ATM-dependent cell cycle checkpoint activation (Kobayashi et al, 2009;Aydin et al, 2014). In DSB damage-dependent histone modification, γ-H2AX is of great importance for the effective operation of DSB damage responses.…”

Section: Introductionmentioning

confidence: 99%

“…These actions result in the catalytic activation of ATR through direct binding of the ATR-ATRIP complex to the activation domain of TopBP1 (Nam and Cortez, 2011). ATR-deficient Seckel syndrome is reported to have certain phenotypes in common with NBS, such as microcephaly and abnormal regulation of centrosome replication (Shimada et al, 2009;Nam and Cortez, 2011). NBS patient cells also show significant decreases in the ATR-related phosphorylation of proteins such as Chk1 and p53 following hydroxyurea treatment, and fail to restart stalled replication (Stiff et al, 2005;Jazayeri et al, 2006).…”

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confidence: 99%

Chromatin modification and NBS1: their relationship in DNA double-strand break repair

2015

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The importance of chromatin modification, including histone modification and chromatin remodeling, for DNA double-strand break (DSB) repair, as well as transcription and replication, has been elucidated. Phosphorylation of H2AX to γ-H2AX is one of the first responses following DSB detection, and this histone modification is important for the DSB damage response by triggering several events, including the accumulation of DNA damage response-related proteins and subsequent homologous recombination (HR) repair. The roles of other histone modifications such as acetylation, methylation and ubiquitination have also been recently clarified, particularly in the context of HR repair. NBS1 is a multifunctional protein that is involved in various DNA damage responses. Its recently identified binding partner RNF20 is an E3 ubiquitin ligase that facilitates the monoubiquitination of histone H2B, a process that is crucial for recruitment of the chromatin remodeler SNF2h to DSB damage sites. Evidence suggests that SNF2h functions in HR repair, probably through regulation of end-resection. Moreover, several recent reports have indicated that SNF2h can function in HR repair pathways as a histone remodeler and that other known histone remodelers can also participate in DSB damage responses. On the other hand, information about the roles of such chromatin modifications and NBS1 in non-homologous end joining (NHEJ) repair of DSBs and stalled fork-related damage responses is very limited; therefore, these aspects and processes need to be further studied to advance our understanding of the mechanisms and molecular players involved.

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“…Additionally, DNA repair factors associate with the centrosomes in different cell types and have centrosomal roles (31). For example, the proteins NBS1 and BRCA1 are involved in centrosome number maintenance (32,33) and the ATM/ATR kinases phosphorylate the centrosome protein CEP63 and regulate the spindle checkpoint after DNA damage (34).…”

Section: Introduction: the Centrosome -An Organizing Center Of Multipmentioning

confidence: 99%

Revisiting the tubulin folding pathway: new roles in centrosomes and cilia

Gonçalves¹,

Tavares²,

Carvalhal³

et al. 2010

BioMolecular Concepts

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Centrosomes and cilia are critical eukaryotic organelles which have been in the spotlight in recent years given their implication in a myriad of cellular and developmental processes. Despite their recognized importance and intense study, there are still many open questions about their biogenesis and function. In the present article, we review the existing data concerning members of the tubulin folding pathway and related proteins, which have been identified at centrosomes and cilia and were shown to have unexpected roles in these structures.

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Inactivation of the Nijmegen Breakage Syndrome Gene Leads to Excess Centrosome Duplication via the ATR/BRCA1 Pathway

Cited by 29 publications

References 47 publications

Differential role of repair proteins, BRCA1/NBS1 and Ku70/DNA‐PKcs, in radiation‐induced centrosome overduplication

Differential role of repair proteins, BRCA1/NBS1 and Ku70/DNA‐PKcs, in radiation‐induced centrosome overduplication

Chromatin modification and NBS1: their relationship in DNA double-strand break repair

Revisiting the tubulin folding pathway: new roles in centrosomes and cilia

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