# The effect of cancer-associated missense mutations in XPA on nucleotide excision repair activity and platinum-based chemotherapy response > **NIH NIH F32** · VANDERBILT UNIVERSITY · 2021 · $43,665 ## Abstract PROJECT SUMMARY/ABSTRACT Nucleotide excision repair (NER) is the primary method to repair DNA adducts formed by platinum (Pt)-based chemotherapies, such as cisplatin. Stratifying cancer patients based on mutations in NER genes that disrupt NER activity and sensitize cells to Pt-based chemotherapeutics represents a promising precision medicine strategy. To address this opportunity, the long-term objectives of this proposal are (i) to develop a robust pipeline that can derive validated, phenotypic insights from patient genomic data, and (ii) benchmark this pipeline on the essential NER scaffold protein, Xeroderma Pigmentosum Complementation Group A (XPA). A computational approach will be developed to predict missense mutations in XPA that disrupt NER activity by integrating protein stability modeling, proximity to known disease-causing mutations, secondary structure prediction, and evolutionary conservation. Predicted deleterious mutations in XPA will be functionally validated by in vitro and cell-based NER activity assays, as well as by cell survival assays after treatment with cisplatin. The mechanism of NER dysfunction and cisplatin sensitivity for a subset of validated mutations in XPA will be determined using multiple biophysical and structural approaches, including analyses of DNA binding affinity, secondary structure and stability, three-dimensional structure, and interactions with NER pre-incision complex proteins. Completion of this proposal will provide mechanistic insights into how a subset of missense mutations in XPA from tumor genomic data disrupt NER activity and ultimately sensitize cells to cisplatin. Accurately selecting good- versus poor-responders to Pt-based chemotherapy treatment has potential to improve patient quality of life and overall survival, allow for earlier implementation of alternative strategies for poor-responders, and decrease unnecessary costs of care. In addition, this proposal will lay the foundation for a robust strategy capable of deriving mechanistic insights into cell phenotype from genomic data, that can be extended to all core NER pathway proteins or applied to other clinically-relevant pathways. Importantly, completion of this proposal will equip the applicant with a uniquely versatile, multidisciplinary skillset that will greatly enhance the applicant’s potential and career as a future independent investigator. Support from the selected institution and Sponsor, regular progress meetings with the co-sponsoring team and collaborators, strong multi-tiered mentoring, and participation at national conferences will ensure the applicant receives a well-rounded training experience for the duration of this fellowship. ## Key facts - **NIH application ID:** 10204709 - **Project number:** 5F32CA250258-02 - **Recipient organization:** VANDERBILT UNIVERSITY - **Principal Investigator:** Alexandra M Blee - **Activity code:** F32 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2021 - **Award amount:** $43,665 - **Award type:** 5 - **Project period:** 2020-04-01 → 2021-10-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10204709 ## Citation > US National Institutes of Health, RePORTER application 10204709, The effect of cancer-associated missense mutations in XPA on nucleotide excision repair activity and platinum-based chemotherapy response (5F32CA250258-02). Retrieved via AI Analytics 2026-06-04 from https://api.ai-analytics.org/grant/nih/10204709. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*