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dc.contributor.advisorGergely, Fanni
dc.contributor.authorBarr, Alexis
dc.date.accessioned2010-12-14T15:49:49Z
dc.date.available2010-12-14T15:49:49Z
dc.date.issued2010-10-12
dc.identifier.citationBarr A.R, Kilamrtin J.V, Gergely F. CDK5RAP2 functions in centrosome to spindle pole attachment and DNA damage response. Journal Cell Biology, 189:23-29.en_GB
dc.identifier.otherPhD.33487
dc.identifier.urihttp://www.dspace.cam.ac.uk/handle/1810/228639
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/228639
dc.description.abstractThe centrosome is the major microtubule organising centre in vertebrate cells. CDK5RAP2 is a human protein that localises to the centrosome. At the start of this thesis work, the function of CDK5RAP2 was uncharacterised. Significantly, cdk5rap2 is one of several centrosomal genes that are mutated in the developmental disorder Primary Microcephaly, where affected individuals have smaller brains than expected for the age- and sex-adjusted mean. Orthologues of CDK5RAP2 in the fruit fly (Centrosomin/Cnn) and in fission yeast (Mod20p) have been well characterised and are known to have important roles in maintaining centrosome structure and in regulating microtubule nucleation. CDK5RAP2 shares two evolutionarily conserved domains with Cnn, known as CNN motif 1 and 2. Using the chicken B-cell line, DT40, I have used gene-targeting methods to disrupt both of these domains in CDK5RAP2. This revealed a function for CDK5RAP2 in attaching centrosomes to mitotic spindle poles. Centrosome attachment to spindle poles is mediated by a binding partner of CDK5RAP2, AKAP450. AKAP450 also localises to centrosomes and provides anchorage sites for spindle poles in the centrosome. Disruption of the CNN1 and CNN2 domains of CDK5RAP2 causes mislocalisation of AKAP450 from the centrosome and detachment of centrosomes from spindle poles. My studies in DT40 and in human cell lines revealed that CDK5RAP2 and AKAP450 also cooperate during interphase to maintain the two centrioles in the centrosome as a pair. In addition to a structural role in the centrosome, I also find that CNN motif 1 of CDK5RAP2 plays a role in the cellular response to DNA damage. In the absence of CNN motif 1, cells no longer efficiently arrest the cell cycle in response to damage. Centrosome-mediated mitotic spindle alignment and the DNA damage response have both been implicated in microcephaly. Therefore, defects in these functions of CDK5RAP2 may explain how mutations in cdk5rap2 may lead to microcephaly.en_GB
dc.description.sponsorshipThis work was sponsored by Cancer Research UK.en_GB
dc.language.isoenen_GB
dc.rightsAll Rights Reserveden
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved/en
dc.subjectCentrosomeen_GB
dc.subjectCDK5RAP2en_GB
dc.subjectMitosisen_GB
dc.subjectAKAP450en_GB
dc.subjectDNA damageen_GB
dc.subjectSpindle Assemblyen_GB
dc.titleCharacterising the function of CDK5RAP2 in the vertebrate centrosomeen_GB
dc.typeThesisen_GB
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameDoctor of Philosophy (PhD)
dc.publisher.institutionUniversity of Cambridgeen_GB
dc.publisher.departmentDepartment of Oncologyen_GB
dc.identifier.doi10.17863/CAM.16183


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