DNA repair and sister chromatid exchange
Date
2008
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Abstract
Mitotic recombination that occurs between sister chromatids, known as sister chromatid exchange (SCE), is a common event in mammalian cells; yet very little is understood about SCE. Likewise, the biological relevance of SCE to humans is also unclear. It is generally thought that SCE represents no permanent alteration to genetic information, however, many cancer prone syndromes present elevated levels of SCE and it is not known whether they are a causal factor in cancer progression or simply a symptom of underlying genomic instability. It has also been purposed that SCE occurring in telomeres (T-SCE) may contribute to the aging phenotype seen in progeroid syndromes. Several accelerated aging syndromes, such as progeria, show highly elevated levels of SCE within telomeric regions. The role of DNA repair in SCE regulation and formation is also under investigation. While it has been shown that at least one of the DNA repair pathways, homologous recombination (HR), is likely to be involved in the formation of SCE, it is less clear whether other DNA repair pathways are also involved in either the formation or suppression of SCE. Therefore, the goal of this research has been to better understand how DNA repair pathways can influence SCE frequency, and how SCE relates to cancer progression and aging. This research also examines how the physical location of SCE, whether it be in genomic (G-SCE) or telomeric (T-SCE) DNA, influence which DNA repair pathways are involved. I examined the role of HR by investigating the Werner (WRN), Bloom (BLM), and FANCD2 proteins. I also investigated the role of non-homologous end joining (NHEJ) by examining the DNA-dependent protein kinase (DNA-PKcs), both the Ku70/80 heterodimer and the catalytic subunit (DNA-PKcs), and Artemis. ERCC1 is a representative member of the final DNA repair pathway examined, nucleotide excision repair (NER). Lastly, I determined if/how DNA repair status can influence the ionizing radiation induced bystander effect (BSE). I was able to determine that at least some of the DNA repair proteins are critical in the generation of a bystander signal providing the first evidence that DNA repair can have an influence via an inter-cellular pathway.
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Subject
aging
cancer
DNA repair
sister chromatid exchange
molecular biology
cellular biology
medicine
oncology