Project 1: The role of acetylation in the non-homologous end joining pathway & Project 2: The identification of human disease genes through the use of exome sequencing

[摘要] Project 1:DNA double-strand breaks (DSBs) are known to be the most deleterious of lesions and if left unrepaired, may result in apoptosis or gross chromosomal rearrangements. The non-homologous end joining (NHEJ) pathway is the main repair pathway for DSBs, and defects in the pathway have been shown to cause genomic instability and contribute to tumourigenesis. It has been shown that post-translational modifications play a large role in the control and regulation of the NHEJ pathway, and therefore present attractive targets to develop new therapies. Several components of the NHEJ pathway, including XLF, XRCC4 and DNA Ligase IV have been suggested to undergo acetylation in response to DNA damage, and it is thought that this may play a role in the regulation of the NHEJ pathway. Following investigation, it was found that these components may become acetylated in vitro, however in vivo, the results were more elusive. The results suggest that XLF and XRCC4 are basally acetylated prior to DNA damage, but may become hyper-acetylated in response to a DSB. If acetylation is confirmed to play a regulatory role in the process of NHEJ, it may provide a target which may be exploited in order to develop novel cancer treatments and therapies. Project 2:Exome sequencing combined with techniques such as autozygosity mapping provides a useful method to examine variants for autosomal recessive diseases. This approach has been used to investigate and identify the causal variants in two Pakistani families with Ichthyosis and two Israeli-Arab families with Cerebral palsy.Autosomal Recessive Congenital Ichthyosis (ARCI) is a rare and genetically heterogeneous disorder characterized by hyperkeratosis in addition to dry, scaly skin. Exome sequencing data for two affected individuals from two Pakistani families were analysed. Candidate variants were screened for in several additional members from each of the families to determine if the mutation segregated. It was found that a mutation in ABCA12 segregated in all affected members across both families. Linkage analysis studies performed suggested that the variant had originated from a common ancestor, which implied that the families may have been distantly related.Cerebral palsy is characterised by non-progressive abnormalities in posture and motor function as a result of a defect in the development of the nervous system. Exome sequencing data was provided for two individuals from two Israeli-Arab families with Cerebral palsy. A novel variant found in HPDL is believed to play a causative role in the Cerebral palsy investigated; however this gene has not been well characterised and so collecting evidence to support this theory will be challenging. The successful identification of disease genes and the improved understanding of their methods of pathogenesis, new potential targets may be discovered through which new treatments, therapies, and methods of diagnosis may be developed.

[发布机构] University:University of Birmingham;Department:School of Clinical and Experiment Medicine, Department of Medicine and Medical Education

[关键词] Q Science;QH Natural history;QH426 Genetics