Open AccessCEP135 isoform dysregulation promotes centrosome amplification in breast cancer cells
Author(s) -
Divya Ganapathi Sankaran,
Alexander J. Stemm-Wolf,
Chad G. Pearson
Publication year - 2019
Publication title -
molecular biology of the cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.463
H-Index - 225
eISSN - 1939-4586
pISSN - 1059-1524
DOI - 10.1091/mbc.e18-10-0674
Subject(s) - centrosome , biology , centriole , microbiology and biotechnology , anaphase , mitosis , cancer research , genetics , cancer , cell cycle
The centrosome, composed of two centrioles surrounded by pericentriolar material, is the cell’s central microtubule-organizing center. Centrosome duplication is coupled with the cell cycle such that centrosomes duplicate once in S phase. Loss of such coupling produces supernumerary centrosomes, a condition called centrosome amplification (CA). CA promotes cell invasion and chromosome instability, two hallmarks of cancer. We examined the contribution of centriole overduplication to CA and the consequences for genomic stability in breast cancer cells. CEP135, a centriole assembly protein, is dysregulated in some breast cancers. We previously identified a short isoform of CEP135, CEP135 mini , that represses centriole duplication. Here, we show that the relative level of full-length CEP135 (CEP135 full ) to CEP135 mini (the CEP135 full:mini ratio) is increased in breast cancer cell lines with high CA. Inducing expression of CEP135 full in breast cancer cells increases the frequency of CA, multipolar spindles, anaphase-lagging chromosomes, and micronuclei. Conversely, inducing expression of CEP135 mini reduces centrosome number. The differential expression of the CEP135 isoforms in vivo is generated by alternative polyadenylation. Directed genetic mutations near the CEP135 mini alternative polyadenylation signal reduces the CEP135 full:mini ratio and decreases CA. We conclude that dysregulation of CEP135 isoforms promotes centriole overduplication and contributes to chromosome segregation errors in breast cancer cells.