Chromatin and other obstacles to base excision repair: potential roles in carcinogenesis
| Autor: | Sarah Delaney, Paul J. Caffrey |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
DNA Ligases
DNA Repair DNA damage Carcinogenesis Health Toxicology and Mutagenesis Toxicology medicine.disease_cause DNA Glycosylases Histones 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Genetics medicine DNA-(Apurinic or Apyrimidinic Site) Lyase Nucleosome Humans Genetics (clinical) DNA Polymerase beta 030304 developmental biology 0303 health sciences Mutation biology food and beverages Base excision repair DNA Chromatin Cell biology Histone DNA Repair Enzymes chemistry Drug Resistance Neoplasm 030220 oncology & carcinogenesis biology.protein DNA Damage |
| Zdroj: | Mutagenesis. 35(1) |
| ISSN: | 1464-3804 |
| Popis: | DNA is comprised of chemically reactive nucleobases that exist under a constant barrage from damaging agents. Failure to repair chemical modifications to these nucleobases can result in mutations that can cause various diseases, including cancer. Fortunately, the base excision repair (BER) pathway can repair modified nucleobases and prevent these deleterious mutations. However, this pathway can be hindered through several mechanisms. For instance, mutations to the enzymes in the BER pathway have been identified in cancers. Biochemical characterisation of these mutants has elucidated various mechanisms that inhibit their activity. Furthermore, the packaging of DNA into chromatin poses another obstacle to the ability of BER enzymes to function properly. Investigations of BER in the base unit of chromatin, the nucleosome core particle (NCP), have revealed that the NCP acts as a complex substrate for BER enzymes. The constituent proteins of the NCP, the histones, also have variants that can further impact the structure of the NCP and may modulate access of enzymes to the packaged DNA. These histone variants have also displayed significant clinical effects both in carcinogenesis and patient prognosis. This review focuses on the underlying molecular mechanisms that present obstacles to BER and the relationship of these obstacles to cancer. In addition, several chemotherapeutics induce DNA damage that can be repaired by the BER pathway and understanding obstacles to BER can inform how resistance and/or sensitivity to these therapies may occur. With the understanding of these molecular mechanisms, current chemotherapeutic treatment regiments may be improved, and future therapies developed. |
| Databáze: | OpenAIRE |
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