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Chemistry and Biology of Alkyl Phosphotriester Lesions

Award Number: R01CA236204
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/14/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Chemistry and Biology of Alkyl Phosphotriester Lesions - ABSTRACT The human genome is continuously attacked by a variety of endogenous and exogenous genotoxic agents, which can lead to DNA damage and compromise genomic integrity. Alkylating species constitute a ubiquitous class of DNA damaging agents. Aside from forming nucleobase adducts, alkylating agents can also attack one of the non-carbon-bonded oxygen atoms of internucleotide phosphate group to yield backbone alkylation products, i.e. the alkyl phosphotriester (alkyl-PTE) lesions. Although the alkyl-PTE lesions are induced at relatively high frequencies, very little is known about their repair and biological consequences. We hypothesize that unrepaired alkyl-PTE lesions may lead to the development of cancer and other human diseases by compromising the flow of genetic information through inhibiting DNA replication and transcription, and inducing mutations in cells. We also posit that the effects of the alkyl-PTE lesions on DNA replication and transcription may be modulated by the size of the alkyl group conjugated with the backbone phosphate in DNA. Moreover, alkylating agents are among the earliest and most widely prescribed cancer chemotherapeutic agents. Hence, a systematic investigation about how the alkyl-PTE lesions perturb DNA replication and transcription will reveal molecular insights about how exposure to alkylating agents contributes to cancer development, and provide an important knowledge basis for designing better cancer chemotherapeutic agents. To test the above hypothesis, we propose experiments according to three specific aims: Aim #1. To synthesize oligodeoxyribonucleotides (ODNs) harboring site-specifically inserted alkyl-PTE lesions with different flanking sequences; Aim #2. To investigate how the alkyl-PTE lesions perturb the efficiency and fidelity of DNA replication in cells. Aim #3. to examine the transcriptional mutagenesis and repair of alkyl-PTE lesions. The proposed research is built upon our established expertise in the chemical syntheses of lesion-carrying ODNs and in utilizing shuttle vector methods for the assessment about how DNA lesions perturb DNA replication and transcription in cells. The outcome of the proposed studies will provide a systematic and molecule-level understanding about the repair and human health consequences of the alkyl-PTE lesions. Thus, the proposed research will lead to important knowledge for assessing the risk of human exposure toward alkylating agents, for understanding the roles of these lesions in the etiology of human diseases, and for developing better strategies for cancer chemotherapy.


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: 2025 ( Subtotal = $0 )
2025	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Cause and Prevention Research	000	5	4/4/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $353,708 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Cause and Prevention Research	001	5	4/17/2024	NON-COMPETING CONTINUATION	$18,617
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Cause and Prevention Research	000	5	11/15/2023	NON-COMPETING CONTINUATION	$335,091
														Subtotal = $353,708

Issue Date FY: 2023 ( Subtotal = $364,876 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Cause and Prevention Research	001	4	3/31/2023	NON-COMPETING CONTINUATION	$29,785
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Cause and Prevention Research	000	4	11/23/2022	NON-COMPETING CONTINUATION	$335,091
														Subtotal = $364,876

Issue Date FY: 2022 ( Subtotal = $364,876 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	900 UNIVERSITY AVE	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Cause and Prevention Research	001	3	5/6/2022	NON-COMPETING CONTINUATION	$29,784
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	900 UNIVERSITY AVE	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Cause and Prevention Research	000	3	11/4/2021	NON-COMPETING CONTINUATION	$335,092
														Subtotal = $364,876

Issue Date FY: 2021 ( Subtotal = $372,323 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Cause and Prevention Research	000	2	11/24/2020	NON-COMPETING CONTINUATION	$353,707
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Cause and Prevention Research	001	2	1/25/2021	NON-COMPETING CONTINUATION	$18,616
														Subtotal = $372,323

Issue Date FY: 2020 ( Subtotal = $372,323 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Cause and Prevention Research	000	1	12/13/2019	NEW	$363,352
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Cause and Prevention Research	001	1	2/4/2020	NEW	$8,971
														Subtotal = $372,323

Grand Total All Awards = $1,828,106

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Chemistry and Biology of Alkyl Phosphotriester Lesions

Award Number: R01CA236204

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/14/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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