Emerging links among Chromosome Instability (CIN), cancer, and aging

Rao, Chinthalapally V.; Asch, Adam S.; Yamada, Hiroshi

doi:10.1002/mc.22539

Cited by 24 publications

(18 citation statements)

References 152 publications

(209 reference statements)

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“…However, the functional equivalent of SgoL1 mutation (i.e. cohesinopathy, genomic instability, aneuploidy) has been reported frequently in patients with LOAD [26,[37][38][39]73].…”

Section: Shugoshin 1 Haploinsufficient Mice (Sgo1-/+) Showed Cohesinomentioning

confidence: 99%

Critical role of mitosis in spontaneous late-onset Alzheimer’s disease; from a Shugoshin 1 cohesinopathy mouse model

et al. 2018

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From early-onset Alzheimer's disease (EOAD) studies, the amyloid-beta hypothesis emerged as the foremost theory of the pathological causes of AD. However, how amyloid-beta accumulation is triggered and progresses toward senile plaques in spontaneous late-onset Alzheimer's disease (LOAD) in humans remains unanswered. Various LOAD facilitators have been proposed, and LOAD is currently considered a complex disease with multiple causes. Mice do not normally develop LOAD. Possibly due to the multiple causes, proposed LOAD facilitators have not been able to replicate spontaneous LOAD in mice, representing a disease modeling issue. Recently, we reported spontaneous late-onset development of amyloid-beta accumulation in brains of Shugoshin 1 (Sgo1) haploinsufficient mice, a cohesinopathy-mediated chromosome instability model. The result for the first time expands disease relevance of mitosis studies to a major disease other than cancers. Reverse-engineering of the model would shed light on the process of late-onset amyloid-beta accumulation in the brain and spontaneous LOAD development, and contribute to development of interventions for LOAD. This review will discuss the Sgo1 model, our current "three-hit hypothesis" regarding LOAD development with an emphasis on critical role of prolonged mitosis in amyloid-beta accumulation, and implications for human LOAD intervention and treatment. Abbreviations: Alzheimer's disease (AD); Late-onset Alzheimer's disease (LOAD); Early-onset Alzheimer's disease (EOAD); Shugoshin-1 (Sgo1); Chromosome Instability (CIN); apolipoprotein (Apoe); Central nervous system (CNS); Amyloid precursor protein (APP); N-methyl-d-aspartate (NMDA); Hazard ratio (HR); Cyclin-dependent kinase (CDK); Chronic Atrial Intestinal Dysrhythmia (CAID); beta-secretase 1 (BACE); phosphor-Histone H3 (p-H3); Research and development (R&D); Non-steroidal anti-inflammatory drugs (NSAIDs); Brain blood barrier (BBB).

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“…However, the functional equivalent of SgoL1 mutation (i.e. cohesinopathy, genomic instability, aneuploidy) has been reported frequently in patients with LOAD [26,[37][38][39]73].…”

Section: Shugoshin 1 Haploinsufficient Mice (Sgo1-/+) Showed Cohesinomentioning

confidence: 99%

Critical role of mitosis in spontaneous late-onset Alzheimer’s disease; from a Shugoshin 1 cohesinopathy mouse model

et al. 2018

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“…Thus, the concurrent overexpression of WDR62 and TPX2 may lead to centrosome amplification, probably via AURKA activation, in lung cancer cells. Centrosome amplification is known to induce an increase in aberrant mitotic spindle formation, merotelic kinetochore‐microtubule attachment errors, and lagging chromosome formation, all of which can cause chromosome instability . In addition, centrosome amplification is also known to be capable of mimicking and strengthening the effects of oncogenes in triggering cellular invasion .…”

Section: Discussionmentioning

confidence: 99%

“…Centrosome amplification is known to induce an increase in aberrant mitotic spindle formation, merotelic kinetochore-microtubule attachment errors, and lagging chromosome formation, all of which can cause chromosome instability. [22][23][24][25][26][27] In addition, centrosome amplification is also known to be capable of mimicking and strengthening the effects of oncogenes in triggering cellular invasion. 28 Together with the fact that centrosome amplification is a common feature of LAC, 29,30 centrosome amplification as well as increased cellular proliferation may be involved in the relationship between WDR62 overexpression and the poor prognosis of LAC patients.…”

Section: Discussionmentioning

confidence: 99%

WDR62 overexpression is associated with a poor prognosis in patients with lung adenocarcinoma

Shinmura

Kato

Kawanishi

et al. 2017

Molecular Carcinogenesis

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Human WDR62, which is localized in the cytoplasm including the centrosome, is known to be responsible for primary microcephaly; however, the role of WDR62 abnormality in cancers remains largely unknown. In this study, we aimed to reveal the pathological role of WDR62 abnormality in lung adenocarcinoma (LAC). We first examined the WDR62 mRNA expression level of LAC (n = 64) using a QRT-PCR analysis and found that WDR62 mRNA transcripts were significantly overexpressed in LAC (P = 0.0432, Wilcoxon matched pairs test). An immunohistochemical analysis for LAC (n = 237) showed that WDR62 proteins were also significantly overexpressed in LAC (P < 0.0001, Mann-Whitney U test). A Kaplan-Meier analysis demonstrated that patients with LAC who exhibit WDR62 overexpression have a short overall survival (P = 0.0378, log-rank test), and a multivariate analysis revealed that WDR62 overexpression was an independent predictor of a poor survival outcome among LAC patients (hazard ratio, 2.032; 95% confidence interval, 1.071-3.777; P = 0.0305). Next, we examined the functional effect of WDR62 overexpression on the lung cancer cell line H1299. WDR62-overexpressing lung cancer cells exhibited an increase in cell growth. Moreover, the concurrent overexpression of WDR62 and TPX2, a WDR62-interacting protein that is also overexpressed in LAC, induced centrosome amplification in the lung cells. Finally, we disclosed that the concurrent overexpression of WDR62 and TPX2 is common in diverse human cancers, using data from the Cancer Genome Atlas. These results suggested that WDR62 overexpression is associated with a poor prognosis in patients with LAC and leads to an increase in the malignant potential of lung cells.

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“…In particular, alterations at the chromosome level that involve the loss of an essential gene, such as chromosome loss and rearrangement, can only be studied in diploid cells because they are lethal in haploids. In humans, chromosome aberrations are often observed in cancer cells as well as in normal cells of elderly individuals, and are implicated in both cancer development and the aging process (Tischfield, 1997;Lengauer et al, 1998;Rao et al, 2017). Thus, it is clearly important to understand the mechanisms and causes leading to chromosome aberrations.…”

Section: Introductionmentioning

confidence: 99%

Homologous recombination is required for recovery from oxidative DNA damage

Hayashi

Umezu

2017

Genes Genet. Syst.

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We have been studying the genetic events, including chromosome loss, chromosome rearrangements and intragenic point mutations, that are responsible for the deletion of a URA3 marker in a loss of heterozygosity (LOH) assay in the yeast Saccharomycess cerevisiae. With this assay, we previously showed that homologous recombination plays an important role in genome maintenance in response to DNA lesions that occur spontaneously in normally growing cells. Here, to investigate DNA lesions capable of triggering homologous recombination, we examined the effects of oxidative stress, a prominent cause of endogenous DNA damage, on LOH events. Treatment of log-phase cells with H 2 O 2 first caused growth arrest and then, during the subsequent recovery, chromosome loss and various chromosome rearrangements were induced more than 10-fold. Further analysis of the rearrangements showed that gene conversion was strongly induced, approximately 100 times more frequently than in untreated cells. Consistent with these results, two diploid strains deficient for homologous recombination, rad52Δ/rad52Δ and rad51Δ/rad51Δ, were sensitive to H 2 O 2 treatment. In addition, chromosome DNA breaks were detected in H 2 O 2 -treated cells using pulsed-field gel electrophoresis. Altogether, these results suggest that oxidative stress induced recombinogenic lesions on chromosomes, which then triggered homologous recombination leading to chromosome rearrangements, and that this response contributed to the survival of cells afflicted by oxidative DNA damage. We therefore conclude that homologous recombination is required for the recovery of cells from oxidative stress.

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Emerging links among Chromosome Instability (CIN), cancer, and aging

Cited by 24 publications

References 152 publications

Critical role of mitosis in spontaneous late-onset Alzheimer’s disease; from a Shugoshin 1 cohesinopathy mouse model

Critical role of mitosis in spontaneous late-onset Alzheimer’s disease; from a Shugoshin 1 cohesinopathy mouse model

WDR62 overexpression is associated with a poor prognosis in patients with lung adenocarcinoma

Homologous recombination is required for recovery from oxidative DNA damage

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