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Loss of rad51 in zebrafish (Danio rerio): a novel Fanconi anaemia model

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cam.restrictionthesis_access_open
cam.supervisorCvejic, Ana
dc.contributor.authorBotthof, Jan Gregor
dc.date.accessioned2018-01-02T10:27:54Z
dc.date.available2018-01-02T10:27:54Z
dc.date.issued2017-12-01
dc.date.updated2017-12-16T17:15:34Z
dc.description.abstractRAD51 is an indispensable homologous recombination protein, necessary for strand invasion and crossing over. It has recently been designated as a Fanconi anaemia (FA) gene, following the discovery of two patients carrying dominant negative mutations. FA is a hereditary DNA repair disorder characterised by various congenital abnormalities, progressive bone marrow failure and cancer predisposition. The cellular and molecular pathology of FA is poorly understood, resulting in a severe lack of effective treatment options. In this thesis, I describe the first viable vertebrate model of RAD51 loss. Phenotypic characterisation of zebrafish rad51 loss-of-function mutants showed that they develop key features of FA, including hypocellular kidney marrow, sensitivity to crosslinking agents and decreased size. Taking advantage of the unique properties of the zebrafish model, I show that some of these symptoms stem from both decreased proliferation, as well as increased apoptosis of embryonic haematopoietic stem and progenitor cells. Co-mutation of p$L was able to rescue the haematopoietic defects seen in the single mutants, but led to tumour development, underscoring the role of rad51 as a tumour suppressor. I further demonstrate that prolonged inflammatory stress can exacerbate the haematological impairment, leading to an additional decrease in kidney marrow cell numbers. In contrast, prolonged aldehyde-derived stress did not induce symptoms in the mutant fish. These findings strengthen the assignment of RAD51 as a Fanconi gene and provide more evidence for the notion that aberrant p53 signalling during embryogenesis leads to the haematological defects seen later in life in FA. It also strengthens the evidence for the involvement of haematopoietic stress, such as inflammation, in the development of bone marrow failure. Further research on this novel zebrafish FA model will lead to a deeper understanding of the molecular basis of bone marrow failure in FA and the cellular role of RAD51.
dc.description.sponsorshipThis research was supported by a European Hematology Association PhD Studentship
dc.identifier.doi10.17863/CAM.17145
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/270293
dc.language.isoen
dc.publisher.collegeDarwin College
dc.publisher.departmentHaematology
dc.publisher.institutionUniversity of Cambridge
dc.rightsNo Creative Commons licence (All rights reserved)
dc.rightsAll Rights Reserveden
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved/en
dc.subjectFanconi anaemia
dc.subjectrad51
dc.subjectzebrafish
dc.subjecthaematology
dc.subjectp53
dc.subjectcancer
dc.subjectinflammation
dc.subjectstem cells
dc.subjectanaemia
dc.subjectbone marrow failure
dc.titleLoss of rad51 in zebrafish (Danio rerio): a novel Fanconi anaemia model
dc.typeThesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameDoctor of Philosophy (PhD)
dc.type.qualificationtitlePhD in Haematology

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