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CDK5RAP2 functions in centrosome to spindle pole attachment and DNA damage response
Open accessAbstract
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.
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“Other genes with protein-coding SNCs (NEK6, STARD9/KIF16A and CDK5RAP2) turn out to be implicated in the regulation of spindle pole assembly as well62–64.”
From A catalog of single nucleotide changes distinguishing modern humans from archaic hominins (2019) · cites this paper as [64]
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Metadata
- Authors
- Barr, A. R., Kilmartin, J. V., & Gergely, F.
- Affiliations
- University of Cambridge (GB)
- MRC Laboratory of Molecular Biology (GB)
- Corresponding author
- Gergely, Fanni
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2010-04-05
- Volume
- 189
- Issue
- 1
- Pages
- 23-39
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC2854379
- OpenAlex
- W2142993158
- Cited by
- 120
- References
- 70
- Citations by year
- 2025: 7 · 2024: 5 · 2023: 8 · 2022: 8 · 2021: 3 · 2020: 9 · 2019: 5 · 2018: 3 · 2017: 9 · 2016: 4 · 2015: 14 · 2014: 14 · 2013: 9 · 2012: 10
- FWCI
- 4.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Spiral (Imperial College London) (submittedVersion, cc-by-nc-sa)
- Funders
- Cancer Research UK
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- CDK5RAP2, centrosome, pericentriolar matrix, centrosomin, DNA damage response, G2 cell cycle arrest, primary microcephaly, neurogenesis, Drosophila melanogaster, DT40 B cells
- MeSH terms
- Animals, Cell Cycle, Cells, Cultured, Chickens, DNA Damage, HeLa Cells, Humans, Spindle Apparatus, Nerve Tissue Proteins, Centrosome, Cell Cycle Proteins, Antigens, Nuclear, Intracellular Signaling Peptides and Proteins
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