Understanding the regulation of endogenous mutagenesis

Shrikhande, Amruta Mukund (2019) Understanding the regulation of endogenous mutagenesis. Doctoral thesis (PhD), University of Sussex.

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There are a number of cellular mechanisms conserved across eukaryotic organisms that prevent or reduce spontaneous mutation rates and maintain genomic stability. Inactivation of processes that reduce the spontaneous mutation rate, can lead to carcinogenesis and ageing. DNA mismatch repair (MMR) proteins increase the fidelity of DNA replication by several orders of magnitude by correcting mismatches and frameshift mutations generated during DNA replication. Mutations in MMR genes are associated with Lynch Syndrome, a cancer predisposition syndrome characterized by elevated mutation rates.

In order to identify gene deletions which, show additive effect when combined with lower MMR activity (hypomorphic MMR), a genome-wide screen was carried out in S. cerevisiae. The genome-wide screen identified more than 163 deletion strains (3.2% of the total number of strains screened), whose deletion resulted in increased mutation rates in MMR compromised cells which suggests their role in compensating for defective MMR. The 163 genes are enriched in multiple biological processes such as DNA repair, DNA replication etc. The screen also revealed 543 deletion strains (10.6% of the total strains screened), which showed a decrease in mutation rate in hypomorphic MMR cells, suggesting mutation rate can also go down when MMR is not functional in cells. The genes resulting in lower mutation rate were enriched in biological processes, including protein metabolism and transport, general cell metabolism and growth. Interestingly, deletion of genes involved in regulation of transcription coupled repair resulted in lower mutation rate, suggesting their potential role in driving mutagenesis.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics > QH0460 Mutations > QH0467 Genetic repair mechanisms
Depositing User: Library Cataloguing
Date Deposited: 08 Jul 2019 10:07
Last Modified: 01 Sep 2021 07:39
URI: http://sro.sussex.ac.uk/id/eprint/84466

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