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Investigating the role of neddylation in the repair of topoisomerase I inhibitor-induced replication damage in colorectal cancer

Award Number: R00CA273171
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Investigating the role of neddylation in the repair of topoisomerase I inhibitor-induced replication damage in colorectal cancer - PROJECT SUMMARY Colorectal cancer (CRC) is one of the most lethal cancers. The topoisomerase I (TOP1) inhibitor irinotecan is a major component of the current chemotherapeutic regimens for treatment of CRC. TOP1 is an enzyme that resolves DNA topological issues by transient DNA breakage. TOP1-DNA cleavage complexes (TOP1ccs) are covalent protein-DNA intermediates formed during TOP1 activity. Clinically active TOP1 inhibitors convert the transient TOP1ccs into long-lived TOP1 DNA-protein crosslinks (TOP1-DPCs). TOP1-DPCs interfere with DNA metabolic processes and induce cell death. Cells can repair TOP1-DPCs using mechanisms such as the ubiquitin-proteasome system (UPS), and enhanced repair capability can result in reduced clinical efficacy of TOP1 inhibitors. Targeting the UPS-dependent repair may improve the therapeutic benefits of TOP1 inhibitors. Following high-throughput screens in CRC cells, I identified pevonedistat, a NEDD8-activating enzyme inhibitor, as a cytotoxic agent inducing synergistic cytotoxicity with irinotecan and other TOP1 inhibitors. I also found that inhibition of NEDD8 modification (neddylation) blocked the proteasomal degradation of TOP1-DPCs. I hypothesize that the DDB1-CUL4-RBX1 complex (CRL4), a ubiquitin E3 ligase that is activated upon neddylation and is important for DNA replication and repair, ubiquitylates TOP1-DPCs leading to their degradation. I found that DCAF13, a DDB1-CRL4 associated factor, binds to TOP1 and is required for TOP1- DPC ubiquitylation, suggesting that DCAF13 recruits TOP1-DPC to CRL4. I will systematically assess this hypothesis and its implications during this award via three specific aims. During the K99 phase, I will work closely with my mentor, Dr. Yves Pommier, a world-renowned expert in topoisomerases and cancer chemotherapy. During my K99 training, I will assess the combination of irinotecan plus pevonedistat in CRC patient-derived preclinical models (Aim 1). In specific aim 2, I will determine if the CRL4 complex acts as a ubiquitin ligase for TOP1-DPCs and determine if DCAF13 is sufficient to recruit TOP1-DPCs for CRL4- mediated ubiquitylation. In addition, I will study the mechanism by which neddylation activates the CRL4 complex for TOP1-DPC repair. Work in aim 2 will continue the independent R00 phase of this grant. A major goal for this latter phase will be to determine CRL4-targeted ubiquitylation sites on TOP1-DPCs using mass spectrometry. These results will be important for understanding mechanisms the allow cells to distinguish between TOP1ccs and long lasting TOP1-DPCs Further experiments in the R00 phase (Aim 3) will interrogate the role of neddylation in the repair of TOP1-DPC-induced DNA double-strand breaks (DSBs) during replication in CRC cells. I will determine if neddylation modifies histones to recruit factors involved in homologous recombination (HR) and if neddylation modifies p53 to enhance p53-regulated HR gene expression to facilitate the DSB repair. Thus, support through the K99/R00 award will be instrumental in completing this important research and will help me successfully transition as an independent researcher.


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 = $224,100 )
2026	2026	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cancer Treatment Research	000	3	12/5/2025	NON-COMPETING CONTINUATION	$224,100
														Subtotal = $224,100

Issue Date FY: 2025 ( Subtotal = $249,000 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cancer Treatment Research	002	2	6/5/2025	EXTENSION WITH OR WITHOUT FUNDS	$0
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cancer Treatment Research	000	2	2/14/2025	EXTENSION WITH OR WITHOUT FUNDS	$224,100
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cancer Treatment Research	001	2	5/28/2025	EXTENSION WITH OR WITHOUT FUNDS	$24,900
														Subtotal = $249,000

Grand Total All Awards = $473,100

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Investigating the role of neddylation in the repair of topoisomerase I inhibitor-induced replication damage in colorectal cancer

Award Number: R00CA273171

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/01/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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