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Replication Gap Suppression by Translesion Synthesis Promotes Drug Resistance in hard-to-treat cancers

Award Number: F99CA305484
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/26/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Replication Gap Suppression by Translesion Synthesis Promotes Drug Resistance in hard-to-treat cancers - Project Summary/Abstract Glioblastoma and pancreatic cancers are among the most aggressive and drug-resistant cancers with poor prognosis and low survival rates. As current therapeutic interventions, which consist of surgical resection followed by radiation and chemotherapy, rely on DNA damage effects, there is an urgent need for new therapeutic strategies to improve outcomes for these patients. A key mechanism contributing to drug resistance in cancer is replication gap suppression (RGS), which helps maintain genomic stability by controlling single-stranded DNA (ssDNA) gaps that affect cell fitness during replication stress. Translesion synthesis (TLS), a process involving specialized DNA polymerases that bypass DNA lesions, plays a central role in RGS, allowing cancer cells to continue proliferating despite DNA damage. However, the mechanism remains unknown. The premise of this study is supported by published and preliminary data that shows: 1) a TLS polymerase kappa (Pol κ) is overexpressed in glioblastoma. 2) early doctoral findings show that Pol κ regulates RGS and fork speed in glioblastoma, processes essential for cancer cell survival. 3) my doctoral research has identified two novel roles of Pol κ: a) Pol κ prevents the accumulation of ssDNA gaps in glioma cells by preventing repriming by Primase DNA polymerase (PrimPol). b) Pol κ slows replication fork speed by promoting the fork reversal repair pathway. This research aims to test the central hypothesis that TLS polymerases enable tumor survival by facilitating the continuation of DNA replication without generating ssDNA gaps that limit cell fitness. Inhibiting TLS promotes ssDNA gap formation and enhances the sensitivity of cancers to standard therapeutics that generate extensive DNA damage that blocks the normal replicative polymerases. During the F99 phase, Aim 1a. will investigate whether Pol κ reduces ssDNA gaps produced from PrimPol by filling these gaps. In this approach, I first use polymerase extension assay to determine the role of Pol κ in extending synthetic substrates with ssDNA gaps. Aim1b. will determine the Pol κ’s mechanism in fork reversal by using enzymatic activity assays to measure changes in the specificity constant (kcat/KM) for Pol κ-mediated fork reversal. Aim 1c. will determine Pol κ interacting proteins during DNA replication using quantitative proteomics approaches TAP-MS and iPOND-MS. During the K00 phase, I will shift my focus to characterizing the architecture of ssDNA gaps and assessing TLS polymerase activity in pancreatic cancer cells. I will involve nanopore sequencing to determine the positions, numbers, and size of the ssDNA gaps in the context of TLS polymerase inhibition to enhance cancer cell sensitivity to DNA-damaging agents. To complete these aims, I have assembled a mentoring team of leaders in cancer research and drug resistance with expertise in enzymology, proteomics, and genomics approaches. These new approaches, combined with my already strong background in genetics, cell biology, molecular biology, and biochemistry, will allow me to address the most challenging issues facing standard therapeutics in challenging cancers and prepare me to pursue a career as an independent academic investigator.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $3,000 )
2026	2026	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Cancer Cause and Prevention Research	000	1	5/27/2026	SUPPLEMENT FOR EXPANSION	$3,000
														Subtotal = $3,000

Issue Date FY: 2025 ( Subtotal = $41,511 )
2025	2025	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Cancer Cause and Prevention Research	000	1	7/29/2025	NEW	$41,511
														Subtotal = $41,511

Grand Total All Awards = $44,511

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Replication Gap Suppression by Translesion Synthesis Promotes Drug Resistance in hard-to-treat cancers

Award Number: F99CA305484

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/26/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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