Date of Award

8-2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Life Sciences

Major Professor

Yie Liu

Committee Members

Brynn H. Voy, Mariano Labrador, Kurt H. Lamour

Abstract

Telomeres are the chromosome end structures consisting of telomere-associated proteins and short tandem repeat sequences, TTAGGG, in humans and mice. Telomeres prevent chromosome termini from being recognized as broken DNA ends. The structural integrity of DNA including telomeres is constantly threatened by a variety of DNA damaging agents on a daily basis. To counteract the constant threats from DNA damage, organisms have developed a number of DNA repair pathways to ensure that the integrity of genome remains intact. A number of DNA repair proteins localize to telomeres and contribute to telomere maintenance; however, it is still unclear as to what extent.

Telomere shortening has been linked to rare human disorders that present with bone marrow failure including Fanconi anemia (FA). FANCC is one of the most commonly mutated FA genes in FA patients and the FANCC subtype tends to have a relatively early onset of bone marrow failure and hematologic malignancies. Here, we studied the role of Fancc in telomere length regulation in mice. We demonstrated that deletion of Fancc did not affect telomerase activity, telomere length or telomeric end-capping in mice with long telomeres. We also showed that Fancc deficiency accelerates telomere shortening during high turnover of hematopoietic cells and promotes telomere recombination initiated by short telomeres.

Telomere shortening has also been linked to human aging and cancer development, with oxidative stress as a major contributing factor. 8-oxo-7, 8-dihydroguanine is among the most common oxidative DNA lesions, and is substrates for OGG1-initiated DNA base excision repair. Mammalian telomeres consist of triple guanine repeats and are subject to oxidative guanine damage. Here, we investigated the impact of oxidative guanine damage and its repair by OGG1 on telomere integrity. We demonstrated that oxidative guanine damage can arise in telomeres where it affects length homeostasis, recombination, DNA replication, and DNA breakage repair. We also examined if telomeric DNA is particularly susceptible to oxidative guanine damage and if telomere specific factors affect the incision of oxidized guanines by OGG1. We showed that the GGG sequence context of telomere repeats and certain telomere configurations may contribute to telomere vulnerability to oxidative DNA damage processing.

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