CENP-A overexpression promotes aneuploidy with karyotypic heterogeneity

Shrestha, Roshan L.; Rossi, Austin; Wangsa, Darawalee; Hogan, Ann; Zaldana, Kimberly S; Suva, Evelyn; Chung, Yang Jo; Sanders, Chelsea; Difilippantonio, Simone; Karpova, Tatiana S.; Karim, Baktiar O.; Foltz, Daniel R.; Fachinetti, Daniele; Aplan, Peter D.; Ried, Thomas; Basrai, Munira A.

doi:10.1083/jcb.202007195

Cited by 32 publications

(48 citation statements)

References 113 publications

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“…Increased ectopic CENP-A directly correlates with mitotic defects [46,116]. As mentioned above, overexpressed CENP-A can weaken the endogenous kinetochore [46,99] royalsocietypublishing.org/journal/rsob Open Biol. 11: 210189…”

Section: Cenp-a Mislocalization and Cancersmentioning

confidence: 86%

“…These cells exhibit lagging chromosome, micronuclei formation and abnormal mitotic exit [34,45,46]. It has been shown that overexpression of CENP-A in human cells causes reduced kinetochores in native centromeres and unstable kinetochore-microtubule interaction, which may contribute to the cellular defects in these cells [46,99]. Overexpression of CENP-A also leads to misregulation of gene expression, which can also contribute to the defects [99][100][101].…”

Section: Mislocalization Of Cenp-a Has Deleterious Effect On Chromosome Segregationmentioning

confidence: 99%

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Recent insights into mechanisms preventing ectopic centromere formation

et al. 2021

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The centromere is a specialized chromosomal structure essential for chromosome segregation. Centromere dysfunction leads to chromosome segregation errors and genome instability. In most eukaryotes, centromere identity is specified epigenetically by CENP-A, a centromere-specific histone H3 variant. CENP-A replaces histone H3 in centromeres, and nucleates the assembly of the kinetochore complex. Mislocalization of CENP-A to non-centromeric regions causes ectopic assembly of CENP-A chromatin, which has a devastating impact on chromosome segregation and has been linked to a variety of human cancers. How non-centromeric regions are protected from CENP-A misincorporation in normal cells is largely unexplored. Here, we review the most recent advances on the mechanisms underlying the prevention of ectopic centromere formation, and discuss the implications in human disease.

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Section: Cenp-a Mislocalization and Cancersmentioning

confidence: 86%

Section: Mislocalization Of Cenp-a Has Deleterious Effect On Chromosome Segregationmentioning

confidence: 99%

Recent insights into mechanisms preventing ectopic centromere formation

et al. 2021

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“…Interestingly, High-level CENPA in ccRCC is consistent with the CIN in cancer. In addition, CENPA overexpression promotes aneuploidy with karyotypic heterogeneity [ 36 ]. Therefore, we deduced that chromosomal aneuploidy caused by CENPA overexpression is an important cause of ccRCC.…”

Section: Discussionmentioning

confidence: 99%

CENPA promotes clear cell renal cell carcinoma progression and metastasis via Wnt/β-catenin signaling pathway

Wang

Zhang

et al. 2021

J Transl Med

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Clear cell renal cell carcinoma (ccRCC) is the most common malignant tumor of the kidney. New and reliable biomarkers are in urgent need for ccRCC diagnosis and prognosis. The CENP family is overexpressed in many types of cancers, but its functions in ccRCC have not been fully clarified. In this paper, we found that several CENP family members were highly expressed in ccRCC tissues. Also, CENPA expression level was related to clinicopathological grade and prognosis by weighted gene co-expression network analysis (WGCNA). CENPA served as a representative CENP family member as a ccRCC biomarker. Further in vitro experiments verified that overexpression of CENPA promoted ccRCC proliferation and metastasis by accelerating the cell cycle and activating the Wnt/β-catenin signaling pathway. The elevated β-catenin led by CENPA overexpression translocated to nucleus for downstream effect. Functional recovery experiment confirmed that Wnt/β-catenin pathway was essential for ccRCC progression and metastasis. Developing selective drugs targeting CENPA may be a promising direction for cancer treatment.

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“…Evidence from human cells shows that CENP-A incorporation in ectopic sites leads to the recruitment of other centromeric components. In cancer cells, CENP-A overexpression can be detrimental, leading to neocentromere formation, chromosomal instability and growth advantage, increasing tumour malignancy [28].…”

Section: Epigenetics Approaches To Explore the Architecture Of Centromeric Chromatinmentioning

confidence: 99%

“…The molecular consequences of CENP-A overexpression in cancer cells are still unclear [25][26][27]. However, CENP-A overexpression drives chromosomal instability and aneuploidy, as shown in a cancer cell line and in a xenograft mouse model [28].…”

Section: Introductionmentioning

confidence: 99%

Emerging Single-Cell Technological Approaches to Investigate Chromatin Dynamics and Centromere Regulation in Human Health and Disease

Leo

Romano

2021

IJMS

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Epigenetic regulators play a crucial role in establishing and maintaining gene expression states. To date, the main efforts to study cellular heterogeneity have focused on elucidating the variable nature of the chromatin landscape. Specific chromatin organisation is fundamental for normal organogenesis and developmental homeostasis and can be affected by different environmental factors. The latter can lead to detrimental alterations in gene transcription, as well as pathological conditions such as cancer. Epigenetic marks regulate the transcriptional output of cells. Centromeres are chromosome structures that are epigenetically regulated and are crucial for accurate segregation. The advent of single-cell epigenetic profiling has provided finer analytical resolution, exposing the intrinsic peculiarities of different cells within an apparently homogenous population. In this review, we discuss recent advances in methodologies applied to epigenetics, such as CUT&RUN and CUT&TAG. Then, we compare standard and emerging single-cell techniques and their relevance for investigating human diseases. Finally, we describe emerging methodologies that investigate centromeric chromatin specification and neocentromere formation.

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CENP-A overexpression promotes aneuploidy with karyotypic heterogeneity

Cited by 32 publications

References 113 publications

Recent insights into mechanisms preventing ectopic centromere formation

Recent insights into mechanisms preventing ectopic centromere formation

CENPA promotes clear cell renal cell carcinoma progression and metastasis via Wnt/β-catenin signaling pathway

Emerging Single-Cell Technological Approaches to Investigate Chromatin Dynamics and Centromere Regulation in Human Health and Disease

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