# DNA ligase activities during base excision repair coordination > **NIH NIH R35** · UNIVERSITY OF FLORIDA · 2024 · $374,065 ## Abstract PROJECT SUMMARY Base excision repair (BER) is a critical mechanism for preventing the mutagenic and lethal consequences of DNA damage generated by endogenous reactive chemical species or exposure to environmental hazards. BER is multi-step pathway that requires a tight coordination between the repair proteins. The downstream steps of BER pathway involves gap filling by DNA polymerase (pol) β and subsequent nick sealing by DNA ligase (ligase I or IIIα). This step-to-step coordination is orchestrated by non-enzymatic scaffolding protein X-Ray Repair Cross Complementing 1 (XRCC1) that plays a key role in assembling repair proteins. Although the roles of the individual enzymes are largely studied, how the multi-protein BER complex coordinates while maintaining the repair efficiency remains unclear. Though often considered an accurate process, the BER can contribute to genome instability if normal coordination breaks down. For example, the mutations in the polβ gene that have been found in many human cancers result in the modifications in its repair functions that impair BER efficiency. Similarly, XRCC1 cancer-associated variants with a defective scaffolding role predispose the cell to genomic instability and transformation. Failure in the BER pathway coordination could result in the formation of strand-break repair intermediates that are more mutagenic or toxic than the initial DNA lesions. My research program will fill the important gap of knowledge in the BER field by elucidating the molecular components of multi-protein BER complex that are necessary for accurate repair and define the ramifications of defective pathway coordination during DNA ligase I and IIIα activities. We are in a unique position to advance this scientific front based on our strong track record and our multidisciplinary approach. In Project 1, we build off our substantial prior work using biochemical and biophysical approach to define the molecular mechanism by which polβ, DNA ligases I and IIIα execute the repair pathway coordination. Our studies will also elucidate cancer-associated XRCC1 and polβ variants with altered BER functions as an important determinants of defective pathway coordination. In Project 2, using X-ray crystallography, we will elucidate the features of DNA substrate and ligase interaction that dictate accurate versus mutagenic outcomes during final nick sealing step at atomic resolution. This project will be extended with cryo-EM to define the structural architecture of large BER multi-protein complexes scaffolded by XRCC1 that dictates accurate repair pathway coordination. With these 2 Projects, my laboratory will launch a new and unique aspect of the research conducted by my group which seeks to better understand the mechanism by which a multi-protein repair complex coordinate during BER and answer several key questions regarding how a tight coordination is vital for maintaining the integrity of our genomic DNA, functions normally and how altering these f... ## Key facts - **NIH application ID:** 10850653 - **Project number:** 5R35GM147111-03 - **Recipient organization:** UNIVERSITY OF FLORIDA - **Principal Investigator:** MELIKE CAGLAYAN - **Activity code:** R35 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $374,065 - **Award type:** 5 - **Project period:** 2022-08-15 → 2027-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10850653 ## Citation > US National Institutes of Health, RePORTER application 10850653, DNA ligase activities during base excision repair coordination (5R35GM147111-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10850653. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*