# The Molecular Mechanism of Genetic Disorders Due to XPD Mutations

> **NIH NIH F31** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2024 · $42,574

## Abstract

PROJECT SUMMARY
Nucleotide excision repair (NER) is a crucial DNA repair pathway that removes bulky and helical-distorting
lesions (e.g., UV damage) from the genome. NER has two subpathways: Transcription Coupled NER (TC-
NER), which repairs damage on the transcribed strand when RNA polymerase II (RNA Pol II) is stalled by the
damage, and Global Genomic NER (GG-NER), which repairs damage everywhere else in the genome when
damage is recognized by XPC/UV-DDB proteins. After damage recognition, these subpathways converge with
the recruitment of Transcription Factor IIH (TFIIH), a 10-subunit protein complex responsible for unwinding the
DNA strands to allow DNA incision on the damaged strand. The DNA unwinding function is conducted by XPD,
a DNA helicase in TFIIH, with the assistance of other subunits. Mutations of the XPD gene are associated with
two genetic disorders: Xeroderma Pigmentosum (XP) and Xeroderma Pigmentosum in combination with
Cockayne Syndrome (XP/CS). XP is characterized by extreme sensitivity to UV light and predisposition to skin
cancer. XP/CS is characterized by neurodegeneration and predisposition to skin cancer. While the
relationship between XPD and human genetic disorders has long been established, why mutations in
the same gene cause clinically distinct phenotypes is currently unclear. The objective of this F31
proposal is to determine DNA repair defects caused by XPD mutations, thereby providing mechanistic insights
into XP and XP/CS symptoms associated with the mutated XPD gene. We have identified a difference
between XP and XP/CS mutants in the overall repair capacity of UV damage using yeast as the model system.
This led to my hypothesis that XPD mutations associated with XP or XP/CS differentially affect GG- and TC-
NER. To test this hypothesis, Aim 1 will use cyclobutane pyrimidine dimer sequencing (CPD-seq), a genome-
wide and strand-specific UV damage sequencing technique, to identify defects in GG- and TC-NER in XPD
mutant cells. Repair defects in GG- and TC-NER could be due to impairment in TFIIH’s DNA helicase activity.
In Aim 2, I will purify TFIIH protein complex and conduct in vitro biochemical assays to investigate how each
XPD mutation impacts TFIIH’s helicase function in DNA unwinding. The neurodegeneration symptom in CS
patients is linked with insufficient repair of endogenous small base damage (e.g., oxidative and alkylation);
however, the involvement of TFIIH in this repair pathway has not been analyzed previously. In Aim 3 I will
determine the impact of XPD mutations on the repair of non-helix-distorting alkylation damage using N-
methylpurine sequencing (NMP-seq), a novel sequencing technique developed by our lab. Overall, I will utilize
multidisciplinary approaches, including genomics, bioinformatics, and biochemistry to tackle a long-standing
question in the DNA repair field. Completion of this project will provide new insights into the mechanism for
NER-associated human diseases.

## Key facts

- **NIH application ID:** 10997069
- **Project number:** 1F31GM156072-01
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Allyson Lynne Hoag
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $42,574
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997069

## Citation

> US National Institutes of Health, RePORTER application 10997069, The Molecular Mechanism of Genetic Disorders Due to XPD Mutations (1F31GM156072-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10997069. Licensed CC0.

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