Protein Dynamics in Mammalian Genome Maintenance

The integrity of the genome, carrier of the blueprint for each organism, is under constant attack from environmental as well as endogenous DNA damaging agents. An agent with substantial impact on our DNA is the UV-fraction of sunlight. It inflicts bulky DNA lesions, which can interfere with vital cellular functions, such as DNA replication and transcription of genes, by simply blocking these processes. This can lead to cell death or to mutations, which in higher organisms can in turn lead to inborn diseases and cancer. To counteract these deleterious effects, the specialized multi-component nucleotide excision repair (NER) machinery has evolved which removes and replaces the damaged oligonucleotide in a multi-step process. Defects in this repair pathway are the underlying cause for the inherited UV-sensitive diseases xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. In association with these disorders it has been demonstrated that repair deficiencies do not only lead to mutations and cancer, but also to developmental difficulties, (neuronal) degeneration and premature ageing. In rapidly dividing cells, not all DNA lesions can be repaired by the time a new DNA replication round has begun, even if the corresponding repair pathway is fully functional. Therefore, cells have also evolved specialized lesion-bypass polymerases. Translesion polymerases are capable of resolving DNA polymerase complexes stalled at DNA damage sites by inserting a nucleotide opposite an altered base, enabling the cell to continue to replicate. Importantly, polymerase eta can insert the correct nucleotide opposite UVinduced pyrimidine-pyrimidine adducts such as cyclobutane pyrimidine dimers (CPD), enabling mutation-free replication of DNA past these UV lesions. Without a functioning polymerase eta, unrepaired UV injuries blocking the replication process can only be resolved by mutational translesion synthesis performed by other lesion bypass polymerases. This leads to a highly elevated risk of skin cancer in patients exhibiting a special form of xeroderma pigmentosum due to lack of polymerase eta.