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The role of polymerase η in protecting against genome instability and telomere defects caused by the generation of environmentally relevant DNA lesions

Pope-Varsalona, Hannah/C (2014) The role of polymerase η in protecting against genome instability and telomere defects caused by the generation of environmentally relevant DNA lesions. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Telomeres, the protective caps at chromosome ends, shorten with age in most human cell types, but may be shortened prematurely by DNA damaging agents. Defective telomeres contribute to aging-related diseases and may give rise to genomic alterations implicated in carcinogenesis. Translesion DNA synthesis is a critical cellular mechanism that ensures progression of DNA replication forks, most notably, in the face of bulky DNA lesions. Numerous environmental exposures generate bulky lesions, such as ultraviolet (UV) light and hexavalent chromium (Cr(VI)). Translesion synthesis polymerase η’s (polη) role in protecting against UV-induced lesions in the genome has been extensively documented, but its role at telomeres is unknown. Additionally, UV-induced lesions have been shown to form at telomeres. Chronic inhalation of Cr(VI) induces respiratory diseases associated with aging and telomere dysfunction, including pulmonary fibrosis and cancers, and our previous work established that Cr(VI) causes telomere damage. However, the mechanism(s) by which environmental genotoxicants promote telomere loss and defects is unknown. We investigated roles for polη in preserving telomeres following acute physical UVC exposure and chronic chemical Cr(VI) exposure. Similar to its role in protecting against UV-induced DNA damage, we report that polη protects against cytotoxicity and DNA replication stress caused by Cr(VI). Our study supports a novel role for translesion DNA synthesis in preserving telomeres after UVC and Cr(VI) exposure and genotoxic stress. We uncover a mechanism by which environmental genotoxicants alter telomere integrity, and a fundamental cellular pathway that preserves telomere function in the face of genotoxic replication stress. Telomere alterations and dysfunction have been shown to impact human health. This research is significant and relevant to public health because knowledge gained will be useful for designing intervention therapies that preserve telomeres in human populations following exposure to environmental genotoxicants. The hope is that preventative measures will inhibit or delay diseases and pathologies related to telomere defects.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Pope-Varsalona, Hannah/Chcp8@pitt.eduHCP8
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorOpresko, Patricia Lplo4@pitt.eduPLO4
Committee ChairBarchowsky, Aaronaab20@pitt.eduAAB20
Committee MemberBakkenist, Christopher Jbakkenistcj@upmc.eduCJB38
Committee MemberPitt, Bruce Rbrucep@pitt.eduBRUCEP
Date: 29 September 2014
Date Type: Publication
Defense Date: 28 July 2014
Approval Date: 29 September 2014
Submission Date: 21 July 2014
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 142
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Environmental and Occupational Health
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: telomeres, translesion synthesis, polymerase η, UV, chromium
Date Deposited: 29 Sep 2014 21:07
Last Modified: 19 Dec 2016 14:42
URI: http://d-scholarship.pitt.edu/id/eprint/22443

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