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Investigating the role of nucleotide excision repair (NER) proteins in the repair of oxidative DNA damage

Kumar, Namrata (2021) Investigating the role of nucleotide excision repair (NER) proteins in the repair of oxidative DNA damage. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

UV-DDB, consisting of subunits DDB1 and DDB2, recognizes UV-induced photoproducts during global genome nucleotide excision repair (GG-NER). We recently demonstrated a noncanonical role of UV-DDB in stimulating base excision repair (BER). This provocative study raised several questions about the timing of UV-DDB arrival at 8-oxoguanine (8-oxoG), and the dependency of UV-DDB on the recruitment of downstream BER and NER proteins. Using two different approaches to introduce 8-oxoG in cells, we show that DDB2 is recruited to 8-oxoG immediately after damage and colocalizes with 8-oxoG glycosylase (OGG1) at sites of repair. Interestingly, OGG1 recruitment to 8-oxoG is significantly reduced in the absence of DDB2. NER proteins, XPA and XPC, also accumulate at 8-oxoG. While XPC recruitment is dependent on DDB2, XPA recruitment is DDB2-independent and transcription-coupled. Finally, DDB2 accumulation at 8-oxoG induces local chromatin unfolding. We propose that DDB2-mediated chromatin decompaction facilitates the recruitment of downstream BER proteins to 8-oxoG lesions.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Kumar, Namratanak147@pitt.edunak1470000-0002-6709-9047
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorVan Houten, Bennettvanhoutenb@upmc.edubev15
Committee ChairOpresko, Patriciaplo4@pitt.eduplo4
Committee MemberArndt, Karenarndt@pitt.edu
Committee MemberO'Sullivan, Roderickrjo@pitt.edu
Committee MemberStewart-Ornstein, Jacobjacobstewartornstein@gmail.com
Date: 17 December 2021
Date Type: Publication
Defense Date: 20 October 2021
Approval Date: 17 December 2021
Submission Date: 23 November 2021
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 171
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Genetics and Developmental Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Base excision repair, Nucleotide excision repair, 8-oxoguanine, oxidative DNA damage, UV-DDB, OGG1, transcription-coupled repair
Date Deposited: 17 Dec 2021 15:06
Last Modified: 17 Dec 2021 15:06
URI: http://d-scholarship.pitt.edu/id/eprint/41973

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