Alcantara, Diana (2013) Understanding at the molecular level the consequences of defective ATR signalling in humans. Doctoral thesis (PhD), University of Sussex.

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Abstract

Ataxia telangiectasia and Rad3-related (ATR) is a central regulator of the mammalian DNA damage response. ATR is essential for survival, but hypomorphic mutations in ATR are associated with a subset of Seckel syndrome (ATR-S), a human condition characterised by microcephaly and severe growth retardation. I used patient-derived cell lines, as well as siRNA ATR inhibition to evaluate the impact of ATR deficiency in skeletal development (osteogenesis and chondrogenesis). The expression of chondroinduction-specific markers was also assessed and found impaired in ATR-S and PCNT-S patient-derived primary fibroblasts. I also found signs of insulin/PI3K/mTOR signalling deregulation in both ATR as well as PCNT deficient cells. A checkpoint defect in a disorder with a primary defect in mTOR pathway function, Donohue Syndrome, was also uncovered, establishing a link between defects in insulin/mTOR signalling with deregulation of the DNA damage response/checkpoint machinery, possibly via the glycogen synthase kinase 3β, GSK3 β, in human patient cells. I characterized cellular functional aspects of a novel microcephalic disorder, Microcephaly-Capillary Malformation Syndrome (MIC-CAP), caused by mutations in the endosome-associated deubiquitinase enzyme STAMBP. MIC-CAP cells exhibit compromised RAS-MAPK and PI3K-AKT pathway signalling, and defective ATR-dependent DDR, a common feature of microcephalic disorders. I also characterized aspects of PI3K-AKT signalling in two megalencephaly disorders harbouring novel mutations in core components of this pathway. Finally, I evaluated aspects of mTOR pathway function in cells from a genomic disorder caused by copy-number variation of 1q21.1.

Item Type:	Thesis (Doctoral)
Schools and Departments:	School of Life Sciences > Biochemistry
Subjects:	Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics
Depositing User:	Library Cataloguing
Date Deposited:	28 Jun 2013 11:49
Last Modified:	10 Sep 2015 15:26
URI:	http://sro.sussex.ac.uk/id/eprint/45246

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