Biomedical Sciences ETDs

Publication Date

Summer 7-28-2026

Abstract

Nucleotide Excision Repair (NER) is a fundamental cellular process that removes bulky and helical distorting lesions from the genome through the separate responses of its two subpathways – global genomic (GG-NER) and transcription coupled (TC-NER) DNA repair. The pathways converge with the recruitment of the TFIIH complex, a key step that is mediated by the translocase and helicase activities of  its XPD subunit. Germline mutations in XPD result in the clinical disorders, Xeroderma Pigmentosum (XP) and XP combined with Cockayne Syndrome (XP/CS). The goal of this thesis was to understand if XPD XP and XP/CS mutations differentially impact GG-NER and TC-NER. Four XPD XP and XP/CS mutations were introduced into the yeast RAD3 gene, a homolog of human XPD. Using CPD sequencing, I found that the XP/CS mutations abrogated repair by both GG-NER and TC-NER, while the XP mutations impaired GG-NER, but altered TC-NER activity to varying extents. I confirmed these results in human cell lines carrying the mutations. I concluded that XPD XP/CS mutations not only cause a more severe NER defect than XP mutations, but by specifically disrupting the TC-NER subpathway, these mutations likely contribute to the clinical symptoms associated with Cockayne Syndrome.

Keywords

DNA Repair; Cockayne Syndrome; Xeroderma Pigmentosum; CPD-seq

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Hua-Ying Fan

Second Committee Member

Alan Tomkinson

Third Committee Member

Peng Mao

Fourth Committee Member

Mary Ann Osley

Fifth Committee Member

Mark McCormick

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