Premature aging syndrome showing random chromosome number instabilities with <i>CDC20</i> mutation

Fujita, Haruyuki; Sasaki, Takashi; Miyamoto, Tatsuo; Akutsu, Silvia Natsuko; Sato, Showbu; Mori, Takehiko; Nakabayashi, Kazuhiko; Hata, Kenichiro; Suzuki, Hisato; Kosaki, Kenjiro; Matsuura, Shinya; Matsubara, Yoichi; Amagai, Masayuki; Kubo, Akiharu

doi:10.1111/acel.13251

Cited by 15 publications

(12 citation statements)

References 43 publications

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“…Pathway analysis of CDC20 interacting proteins suggested additional roles of CDC20 outside cell cycle regulation, with a significant enrichment of specific cellular processes, including protein modification, localization and degradation, telomeres regulation, transcription, and other signaling pathways, as Hippo, TGF-β, β-catenin, MAPK (Table S 1 ). Accordingly, it has been recently shown that CDC20 exerts a pivotal role in different cell type-specific biological processes, as ciliary disassembly [ 87 , 88 ], brain development [ 89 , 90 ], necrosis suppression in neural stem cells under catastrophic cellular stresses [ 91 ], tissue homeostasis and cell fate in human keratinocytes [ 92 , 93 ], genomic stability [ 94 , 95 ], aging [ 96 ] and autophagy [ 97 , 98 ] (Fig. 3 A-D).…”

Section: Main Textmentioning

confidence: 99%

CDC20 in and out of mitosis: a prognostic factor and therapeutic target in hematological malignancies

Bruno

Rorà

Napolitano

et al. 2022

J Exp Clin Cancer Res

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Cell division cycle 20 homologue (CDC20) is a well-known regulator of cell cycle, as it controls the correct segregation of chromosomes during mitosis. Many studies have focused on the biological role of CDC20 in cancer development, as alterations of its functionality have been linked to genomic instability and evidence demonstrated that high CDC20 expression levels are associated with poor overall survival in solid cancers. More recently, novel CDC20 functions have been demonstrated or suggested, including the regulation of apoptosis and stemness properties and a correlation with immune cell infiltration. Here, we here summarize and discuss the role of CDC20 inside and outside mitosis, starting from its network of interacting proteins. In the last years, CDC20 has also attracted more interest in the blood cancer field, being overexpressed and showing an association with prognosis both in myeloid and lymphoid malignancies. Preclinical findings showed that selective CDC20 and APC/CCDC20/APC/CCDH1 inhibitors, namely Apcin and proTAME, are effective against lymphoma and multiple myeloma cells, resulting in mitotic arrest and apoptosis and synergizing with clinically-relevant drugs. The evidence and hypothesis presented in this review provide the input for further biological and chemical studies aiming to dissect novel potential CDC20 roles and targeting strategies in hematological malignancies.

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Section: Main Textmentioning

confidence: 99%

CDC20 in and out of mitosis: a prognostic factor and therapeutic target in hematological malignancies

Bruno

Rorà

Napolitano

et al. 2022

J Exp Clin Cancer Res

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“…12,14,15 Thus, such mutations are rare in human disease, 12,16 and the clinical significance of mutations in CDC20 have been investigated in only a handful of studies in an animal model or human context. [17][18][19][20][21][22][23] Although CDC20 is overexpressed in the majority of human cancers, 16,[24][25][26][27][28][29][30] the involvement of CDC20 mutations in cancer has never been established in humans.…”

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confidence: 99%

“…12,14,15 Thus, such mutations are rare in human disease, 12,16 and the clinical significance of mutations in CDC20 have been investigated in only a handful of studies in an animal model or human context. [17][18][19][20][21][22][23] Although CDC20 is overexpressed in the majority of human cancers, 16,24-30 the involvement of CDC20 mutations in cancer has never been established in humans.In the current study, we originally sought to identify the underlying genetic causes of familial malignant ovarian germ cell tumors (mOGCTs). We identified 8 families with histories of mOGCT.…”

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confidence: 99%

Germline Missense Variants in CDC20 Result in Aberrant Mitotic Progression and Familial Cancer

Chen

Castellsagué

Moustafa-Kamal

et al. 2021

Preprint

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CDC20 is a co-activator of the anaphase promoting complex/cyclosome (APC/C) and is essential for mitotic progression. APC/CCDC20 is inhibited by the spindle assembly checkpoint (SAC), which prevents premature separation of sister chromatids and aneuploidy in daughter cells. Although overexpression of CDC20 is common in many cancers, oncogenic mutations have never been identified in humans. Using whole exome sequencing, we identified heterozygous missense CDC20 variants (L151R and N331K) that segregate with cancer in two families. Characterization of these mutants showed they retain APC/C activation activity but show reduced binding to BUBR1, a component of the SAC. Expression of L151R and N331K promoted mitotic slippage in HeLa cells and primary skin fibroblasts derived from carriers. CRISPR/Cas9 was used to generate mice carrying N331K. Homozygous mice carrying N331K were non-viable, however, heterozygotes displayed accelerated oncogenicity in Myc-driven cancers. These findings highlight an unappreciated role for CDC20 variants as tumor promoting genes in humans.

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“…1 c). Since the human colon cancer cell line HCT116 has two copies of the NBS1 allele and relatively high efficacy of ssODN knock-in 18 , 19 , we transfected both the Cas9-2A-puromycin resistance gene plasmid vector and the ssODN targeting donors into HCT116 cells. After transient puromycin selection for 48 h post-transfection and subsequent culture for 2 weeks, the drug-resistant colonies were isolated, and their genotypes were analyzed by Sca I digestion and direct sequencing of the PCR amplicon of the target locus.…”

Section: Resultsmentioning

confidence: 99%

NBS1 I171V variant underlies individual differences in chromosomal radiosensitivity within human populations

Tomioka

Miyamoto

Akutsu

et al. 2021

Sci Rep

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Genetic information is protected against a variety of genotoxins including ionizing radiation (IR) through the DNA double-strand break (DSB) repair machinery. Genome-wide association studies and clinical sequencing of cancer patients have suggested that a number of variants in the DNA DSB repair genes might underlie individual differences in chromosomal radiosensitivity within human populations. However, the number of established variants that directly affect radiosensitivity is still limited. In this study, we performed whole-exome sequencing of 29 Japanese ovarian cancer patients and detected the NBS1 I171V variant, which is estimated to exist at a rate of approximately 0.15% in healthy human populations, in one patient. To clarify whether this variant indeed contributes to chromosomal radiosensitivity, we generated NBS1 I171V variant homozygous knock-in HCT116 cells and mice using the CRISPR/Cas9 system. Radiation-induced micronucleus formation and chromosomal aberration frequency were significantly increased in both HCT116 cells and mouse embryonic fibroblasts (MEFs) with knock-in of the NBS1 I171V variant compared with the levels in wild-type cells. These results suggested that the NBS1 I171V variant might be a genetic factor underlying individual differences in chromosomal radiosensitivity.

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Premature aging syndrome showing random chromosome number instabilities with CDC20 mutation

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 15 publications

References 43 publications

CDC20 in and out of mitosis: a prognostic factor and therapeutic target in hematological malignancies

CDC20 in and out of mitosis: a prognostic factor and therapeutic target in hematological malignancies

Germline Missense Variants in CDC20 Result in Aberrant Mitotic Progression and Familial Cancer

NBS1 I171V variant underlies individual differences in chromosomal radiosensitivity within human populations

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