Nuclear pore protein NUP88 activates anaphase-promoting complex to promote aneuploidy

Naylor, Ryan M.; Jeganathan, Karthik B.; Cao, Xiwang; Deursen, Jan M. van

doi:10.1172/jci82277

Cited by 37 publications

(31 citation statements)

References 50 publications

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“…In such cases, there is a higher chance of forming syntelic and merotelic attachments because microtubules from different spindle poles approach kinetochores from similar directions, resulting in an increased rate of chromosome missegregation [57,58]. Defective centrosome separation in mouse models was reported to promote aneuploidy and malignant transformation [59][60][61].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Chromosomal instability: A common feature and a therapeutic target of cancer

Tanaka

Hirota

2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Section: Accepted Manuscriptmentioning

confidence: 99%

Chromosomal instability: A common feature and a therapeutic target of cancer

Tanaka

Hirota

2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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“…A subcomplex containing the soluble nuclear pore proteins Nup98 and Rae1 has also been shown to inhibit APC/C Cdh1 activity (62, 63, 100). Nup98-Rae1 binds and inhibits preformed APC/C Cdh1 complexes in late G2 phase in order to prevent the premature degradation of securin and Plk1 (100).…”

Section: The Anaphase-promoting Complex/cyclosomementioning

confidence: 99%

“…Nup98-Rae1 binds and inhibits preformed APC/C Cdh1 complexes in late G2 phase in order to prevent the premature degradation of securin and Plk1 (100). Although it has been shown using in vitro ubiquitination assays that Nup98-Rae1 prevents the APC/C Cdh1 -mediated polyubiquitination of securin (63), the precise mechanism of inhibition is unknown.…”

Section: The Anaphase-promoting Complex/cyclosomementioning

confidence: 99%

Aneuploidy in Cancer and Aging

Naylor¹,

Deursen

2016

Annu. Rev. Genet.

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Chromosomal instability (CIN), the persistent inability of a cell to faithfully segregate its genome, is a feature of many cancer cells. It stands to reason that CIN enables the acquisition of multiple cancer hallmarks; however, there is a growing body of evidence suggesting that CIN impairs cellular fitness and prevents neoplastic transformation. Here, we suggest a new perspective to reconcile this apparent paradox and share an unexpected link between aneuploidy and aging that was discovered through attempts to investigate the CIN-cancer relationship. Additionally, we provide a comprehensive overview of the function and regulation of the anaphase-promoting complex, an E3 ubiquitin ligase that mediates high-fidelity chromosome segregation, and describe the mechanisms that lead to whole-chromosome gain or loss. With this review, we aim to expand our understanding of the role of CIN in cancer and aging with the long-term objective of harnessing this information for the advancement of patient care.

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“…2A). The latter are the result of merotelic attachment, a microtubule-kinetochore malattachment caused by spindle defects, including defects in attachment error correction, microtubule dynamics, mitotic timing, centrosome disjunction, and centrosome movement (9). We systematically screened Ccna2 −/H MEFs for lagging chromosomes, and by measuring the separation between centrosomes in G 2 and prophase, we found that the movement of sister centrosomes to opposite poles was impaired (Fig.…”

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confidence: 99%

Cyclin A2 is an RNA binding protein that controls Mre11 mRNA translation

Kanakkanthara

Jeganathan

Limzerwala

et al. 2016

Science

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Cyclin A2 activates the cyclin-dependent kinases Cdk1 and Cdk2 and is expressed at elevated levels from S phase until early mitosis. We found that mutant mice that cannot elevate cyclin A2 are chromosomally unstable and tumor-prone. Underlying the chromosomal instability is a failure to up-regulate the meiotic recombination 11 (Mre11) nuclease in S phase, which leads to impaired resolution of stalled replication forks, insufficient repair of double-stranded DNA breaks, and improper segregation of sister chromosomes. Unexpectedly, cyclin A2 controlled Mre11 abundance through a C-terminal RNA binding domain that selectively and directly binds Mre11 transcripts to mediate polysome loading and translation.These data reveal cyclin A2 as a mechanistically diverse regulator of DNA replication combining multifaceted kinase-dependent functions with a kinase-independent, RNA binding–dependent role that ensures adequate repair of common replication errors.

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Nuclear pore protein NUP88 activates anaphase-promoting complex to promote aneuploidy

Cited by 37 publications

References 50 publications

Chromosomal instability: A common feature and a therapeutic target of cancer

Chromosomal instability: A common feature and a therapeutic target of cancer

Aneuploidy in Cancer and Aging

Cyclin A2 is an RNA binding protein that controls Mre11 mRNA translation

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