Year: 2008
Type: dissertation
Abstract: The integrity of the genome, carrier of the blueprint for each organism, is\nunder constant attack from environmental as well as endogenous DNA damaging\nagents. An agent with substantial impact on our DNA is the UV-fraction of sunlight. It\ninflicts bulky DNA lesions, which can interfere with vital cellular functions, such as\nDNA replication and transcription of genes, by simply blocking these processes. This\ncan lead to cell death or to mutations, which in higher organisms can in turn lead to\ninborn diseases and cancer. To counteract these deleterious effects, the specialized\nmulti-component nucleotide excision repair (NER) machinery has evolved which\nremoves and replaces the damaged oligonucleotide in a multi-step process. Defects\nin this repair pathway are the underlying cause for the inherited UV-sensitive\ndiseases xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. In\nassociation with these disorders it has been demonstrated that repair deficiencies do\nnot only lead to mutations and cancer, but also to developmental difficulties,\n(neuronal) degeneration and premature ageing. In rapidly dividing cells, not all DNA\nlesions can be repaired by the time a new DNA replication round has begun, even if\nthe corresponding repair pathway is fully functional. Therefore, cells have also\nevolved specialized lesion-bypass polymerases. Translesion polymerases are\ncapable of resolving DNA polymerase complexes stalled at DNA damage sites by\ninserting a nucleotide opposite an altered base, enabling the cell to continue to\nreplicate. Importantly, polymerase eta can insert the correct nucleotide opposite UVinduced\npyrimidine-pyrimidine adducts such as cyclobutane pyrimidine dimers\n(CPD), enabling mutation-free replication of DNA past these UV lesions. Without a\nfunctioning polymerase eta, unrepaired UV injuries blocking the replication process\ncan only be resolved by mutational translesion synthesis performed by other lesion\nbypass polymerases. This leads to a highly elevated risk of skin cancer in patients\nexhibiting a special form of xeroderma pigmentosum due to lack of polymerase eta.
Author: Angelika Zotter
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Award: G7597103732
OpenAlex ID: W2151619932