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CDK5RAP2 functions in centrosome to spindle pole attachment and DNA damage response
The centrosomal protein, CDK5RAP2, is mutated in primary microcephaly, a neurodevelopmental disorder characterized by reduced brain size. The Drosophila melanogaster homologue of CDK5RAP2, centrosomin (Cnn), maintains the pericentriolar matrix (PCM) around centrioles during mitosis. In this study, w...
Autores principales: | , , |
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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2854379/ https://www.ncbi.nlm.nih.gov/pubmed/20368616 http://dx.doi.org/10.1083/jcb.200912163 |
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author | Barr, Alexis R. Kilmartin, John V. Gergely, Fanni |
author_facet | Barr, Alexis R. Kilmartin, John V. Gergely, Fanni |
author_sort | Barr, Alexis R. |
collection | PubMed |
description | The centrosomal protein, CDK5RAP2, is mutated in primary microcephaly, a neurodevelopmental disorder characterized by reduced brain size. The Drosophila melanogaster homologue of CDK5RAP2, centrosomin (Cnn), maintains the pericentriolar matrix (PCM) around centrioles during mitosis. In this study, we demonstrate a similar role for CDK5RAP2 in vertebrate cells. By disrupting two evolutionarily conserved domains of CDK5RAP2, CNN1 and CNN2, in the avian B cell line DT40, we find that both domains are essential for linking centrosomes to mitotic spindle poles. Although structurally intact, centrosomes lacking the CNN1 domain fail to recruit specific PCM components that mediate attachment to spindle poles. Furthermore, we show that the CNN1 domain enforces cohesion between parental centrioles during interphase and promotes efficient DNA damage–induced G2 cell cycle arrest. Because mitotic spindle positioning, asymmetric centrosome inheritance, and DNA damage signaling have all been implicated in cell fate determination during neurogenesis, our findings provide novel insight into how impaired CDK5RAP2 function could cause premature depletion of neural stem cells and thereby microcephaly. |
format | Text |
id | pubmed-2854379 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-28543792010-10-05 CDK5RAP2 functions in centrosome to spindle pole attachment and DNA damage response Barr, Alexis R. Kilmartin, John V. Gergely, Fanni J Cell Biol Research Articles The centrosomal protein, CDK5RAP2, is mutated in primary microcephaly, a neurodevelopmental disorder characterized by reduced brain size. The Drosophila melanogaster homologue of CDK5RAP2, centrosomin (Cnn), maintains the pericentriolar matrix (PCM) around centrioles during mitosis. In this study, we demonstrate a similar role for CDK5RAP2 in vertebrate cells. By disrupting two evolutionarily conserved domains of CDK5RAP2, CNN1 and CNN2, in the avian B cell line DT40, we find that both domains are essential for linking centrosomes to mitotic spindle poles. Although structurally intact, centrosomes lacking the CNN1 domain fail to recruit specific PCM components that mediate attachment to spindle poles. Furthermore, we show that the CNN1 domain enforces cohesion between parental centrioles during interphase and promotes efficient DNA damage–induced G2 cell cycle arrest. Because mitotic spindle positioning, asymmetric centrosome inheritance, and DNA damage signaling have all been implicated in cell fate determination during neurogenesis, our findings provide novel insight into how impaired CDK5RAP2 function could cause premature depletion of neural stem cells and thereby microcephaly. The Rockefeller University Press 2010-04-05 /pmc/articles/PMC2854379/ /pubmed/20368616 http://dx.doi.org/10.1083/jcb.200912163 Text en © 2010 Barr et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Research Articles Barr, Alexis R. Kilmartin, John V. Gergely, Fanni CDK5RAP2 functions in centrosome to spindle pole attachment and DNA damage response |
title | CDK5RAP2 functions in centrosome to spindle pole attachment and DNA damage response |
title_full | CDK5RAP2 functions in centrosome to spindle pole attachment and DNA damage response |
title_fullStr | CDK5RAP2 functions in centrosome to spindle pole attachment and DNA damage response |
title_full_unstemmed | CDK5RAP2 functions in centrosome to spindle pole attachment and DNA damage response |
title_short | CDK5RAP2 functions in centrosome to spindle pole attachment and DNA damage response |
title_sort | cdk5rap2 functions in centrosome to spindle pole attachment and dna damage response |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2854379/ https://www.ncbi.nlm.nih.gov/pubmed/20368616 http://dx.doi.org/10.1083/jcb.200912163 |
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