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Molecular Mechanisms for DNA Damage Processing by Transcription Machinery

Award Number: R01GM102362
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2013
PERIOD OF PERFORMANCE END DATE: 03/31/2027

Group Awards By:

View Award Description

Molecular Mechanisms for DNA Damage Processing by Transcription Machinery - Project Summary/Abstract The long-term goal of this project is to understand how DNA lesions are recognized and repaired in the actively transcribed genome. Harmful DNA lesions, caused by endogenous and environmental agents, must be promptly recognized and repaired in order to avoid deleterious threats to genome integrity. Transcription- coupled nucleotide excision repair (TC-NER) is an important DNA repair pathway as it removes DNA lesions within the transcribed genome. However, little is known about the molecular mechanism of eukaryotic TC-NER initiation. Cockayne Syndrome B protein (CSB), a master TC-NER coordinator, is recruited to the DNA lesion- arrested Pol II site and plays a key role in the initiation of eukaryotic TC-NER. Previously, we reported the first yeast Pol II-Rad26/CSB ternary complex structure, shedding new lights on this important process. However, there is still a fundamental knowledge gap in understanding what happens after CSB recruitment to the DNA lesion-arrested Pol II. Several long-standing questions in the field remain unanswered. First, how does CSB use its DNA translocase activity to remodel the DNA lesion-arrested Pol II and switch Pol II from the transcription elongation mode to the repair mode that leads to the initiation of TC-NER? Second, how is the DNA lesion-arrested Pol II moved away from the DNA lesion to allow the access of repair proteins during TC- NER initiation? Third, are there any missing TC-NER factors that remain to be discovered? If so, how do they fit into this decades-old puzzle? The objective of this proposal is to address these key mechanistic questions in TC-NER initiation. We propose to tackle these challenging questions with an innovative hybrid approach that combines X-ray crystallography, Cryo-EM, computational biology, biochemistry, genetic, and genomic methods. We hypothesize that CSB plays important roles in remodeling lesion-arrested Pol II and coordinates the displacement of elongation factors and Pol II with other repair factors to promote downstream lesion verification steps during the initiation of TC-NER. To test this hypothesis, we propose to investigate the functional interplays between lesion-arrested Pol II complex, Rad26/CSB, and other transcription/repair factors. We propose to elucidate the molecular basis of the enigmatic mechanism of TC-NER initiation. We expect to determine key protein complexes involved in the initiation of TC-NER. Our project has three Specific Aims: Aim 1: Determine the molecular basis of the interplay between Rad26/CSB, Spt4/5, and the DNA lesion- arrested Pol II complex. Aim 2: Elucidate the role of Elf1 in the initiation of TC-NER. Aim 3: Investigate how the lesion-arrested Pol II is displaced during TC-NER initiation. The proposed research is significant and groundbreaking because novel knowledge and structures obtained from this proposal will have a transformative impact on the field of DNA repair field. Ultimately, such knowledge will provide a framework for developing novel TC-NER targeting therapeutics against cancer and other human diseases.


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 = $0 )
2026	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	13	1/20/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $474,422 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	13	3/24/2025	NON-COMPETING CONTINUATION	$426,980
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	13	8/7/2025	NON-COMPETING CONTINUATION	$47,442
														Subtotal = $474,422

Issue Date FY: 2024 ( Subtotal = $474,423 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	12	4/25/2024	NON-COMPETING CONTINUATION	$426,980
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	12	7/15/2024	NON-COMPETING CONTINUATION	$47,443
														Subtotal = $474,423

Issue Date FY: 2023 ( Subtotal = $610,079 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	002	11	7/10/2023	SUPPLEMENT FOR EXPANSION	$135,659
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	11	3/23/2023	NON-COMPETING CONTINUATION	$474,420
2023	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	9	11/18/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $610,079

Issue Date FY: 2022 ( Subtotal = $474,423 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	002	10	3/31/2022	COMPETING CONTINUATION	$474,423
2022	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	9	3/30/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	9	3/29/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $474,423

Issue Date FY: 2021 ( Subtotal = $522,121 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	9	8/6/2021	SUPPLEMENT FOR EXPANSION	$70,263
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	9	2/10/2021	NON-COMPETING CONTINUATION	$451,858
														Subtotal = $522,121

Issue Date FY: 2020 ( Subtotal = $451,858 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	8	1/30/2020	NON-COMPETING CONTINUATION	$406,674
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	8	3/11/2020	NON-COMPETING CONTINUATION	$45,184
														Subtotal = $451,858

Issue Date FY: 2019 ( Subtotal = $451,858 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	7	1/18/2019	NON-COMPETING CONTINUATION	$451,858
														Subtotal = $451,858

Issue Date FY: 2018 ( Subtotal = $451,858 )
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	6	2/1/2018	COMPETING CONTINUATION	$451,858
2018	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	002	5	9/16/2018	NON-COMPETING CONTINUATION	$0
2018	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	5	1/29/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $451,858

Issue Date FY: 2017 ( Subtotal = $443,264 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	5	12/23/2016	NON-COMPETING CONTINUATION	$398,937
2017	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	5	8/7/2017	NON-COMPETING CONTINUATION	$44,327
														Subtotal = $443,264

Issue Date FY: 2016 ( Subtotal = $372,000 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	12/3/2015	EXTENSION WITH OR WITHOUT FUNDS	$265,050
2016	2016	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	4	3/2/2016	EXTENSION WITH OR WITHOUT FUNDS	$29,450
2016	2016	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	002	4	9/2/2016	SUPPLEMENT FOR EXPANSION	$77,500
														Subtotal = $372,000

Issue Date FY: 2015 ( Subtotal = $294,500 )
2015	2015	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	3	2/10/2015	NON-COMPETING CONTINUATION	$29,450
2015	2015	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	3	12/18/2014	NON-COMPETING CONTINUATION	$265,050
														Subtotal = $294,500

Issue Date FY: 2014 ( Subtotal = $294,500 )
2014	2014	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	2	3/11/2014	NON-COMPETING CONTINUATION	$29,450
2014	2014	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	2	2/6/2014	NON-COMPETING CONTINUATION	$265,050
														Subtotal = $294,500

Issue Date FY: 2013 ( Subtotal = $289,902 )
2013	2013	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	12/17/2012	NEW	$289,902
														Subtotal = $289,902

Grand Total All Awards = $5,605,208

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Molecular Mechanisms for DNA Damage Processing by Transcription Machinery

Award Number: R01GM102362

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2013

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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