Analysis of the "centrosome-ome" identifies MCPH1 deletion as a cause of centrosome amplification in human cancer

Ryan A Denu; Mark E Burkard

doi:10.1038/s41598-020-68629-4

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Analysis of the "centrosome-ome" identifies MCPH1 deletion as a cause of centrosome amplification in human cancer

Journal article

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Analysis of the "centrosome-ome" identifies MCPH1 deletion as a cause of centrosome amplification in human cancer

Ryan A Denu and Mark E Burkard

Scientific reports, Vol.10(1), pp.11921-11921

07/17/2020

DOI: 10.1038/s41598-020-68629-4

PMCID: PMC7368085

PMID: 32681070

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Abstract

The centrosome is the microtubule organizing center of human cells and facilitates a myriad of cellular functions including organization of the mitotic spindle to ensure faithful chromosome segregation during mitosis, cell polarization and migration, and primary cilia formation. A numerical increase in centrosomes, or centrosome amplification (CA), is common in cancer and correlates with more aggressive clinical features and worse patient outcomes. However, the causes of CA in human cancer are unclear. Many previous studies have identified mechanisms of CA in cellulo, such as overexpression of PLK4, but it is unclear how often these are the primary mechanism in human disease. To identify a primary cause of CA, we analyzed The Cancer Genome Atlas (TCGA) genomic and transcriptomic data for genes encoding the 367 proteins that localize to the centrosome (the "centrosome-ome"). We identified the following candidates for primary causes of CA: gain-of-function alterations of CEP19, CEP72, CTNNB1, PTK2, NDRG1, SPATC1, TBCCD1; and loss-of-function alterations of CEP76, MCPH1, NEURL4, and NPM1. In cellulo analysis of these candidates revealed that loss of MCPH1/microcephalin caused the most robust increase in centriole number. MCPH1 deep gene deletions are seen in 5-15% of human cancers, depending on the anatomic site of the tumor. Mechanistic experiments demonstrated that loss of MCPH1 caused a CDK2-dependent increase in STIL levels at the centrosome to drive CA. We conclude that loss of MCPH1 is common in human cancer and is likely to be a cause of CA.

Cell Cycle Proteins - genetics

Cell Line, Tumor

Centrioles - metabolism

Centrosome - metabolism

Chromosomal Instability - genetics

Cytoskeletal Proteins - genetics

Gene Deletion

Homozygote

Humans

Neoplasms - genetics

Nucleophosmin

Penetrance

Proteome - metabolism

Tumor Suppressor Protein p53 - metabolism

Details

Title: Subtitle: Analysis of the "centrosome-ome" identifies MCPH1 deletion as a cause of centrosome amplification in human cancer
Creators: Ryan A Denu - University of Wisconsin–Madison
Mark E Burkard - University of Wisconsin–Madison
Resource Type: Journal article
Publication Details: Scientific reports, Vol.10(1), pp.11921-11921
DOI: 10.1038/s41598-020-68629-4
PMID: 32681070
PMCID: PMC7368085
NLM abbreviation: Sci Rep
ISSN: 2045-2322
eISSN: 2045-2322
Grant note: TL1 TR000429 / NCATS NIH HHS F30 CA203271 / NCI NIH HHS P30 CA014520 / NCI NIH HHS T32GM008692 / NIH HHS UL1 TR000427 / NCATS NIH HHS UL1TR000427 / NIH HHS F30CA203271 / NIH HHS R01 GM097245 / NIGMS NIH HHS T32 GM008692 / NIGMS NIH HHS TL1TR000429 / NIH HHS
Language: English
Date published: 07/17/2020
Academic Unit: Internal Medicine
Record Identifier: 9984701256302771

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