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MECHANISMS AND MACROMOLECULAR INTERACTIONS UNDERLYING CELLULAR RESPONSES TO STRESS SIGNALS

Award Number: R35GM144124
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: 04/01/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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MECHANISMS AND MACROMOLECULAR INTERACTIONS UNDERLYING CELLULAR RESPONSES TO STRESS SIGNALS - PROJECT SUMMARY Proteins carrying out DNA repair, replication and transcription, processes essential for the stable transmission and expression of genomic information, share the same track – the DNA – and require delicate coordination to achieve their function. Often, regulation of these processes occurs at the level of targeting or well-timed recruitment, but also catalysis and even turnover of the factor in question. We will address these three principal modalities of regulation in the context of bacterial responses to stress signals. Our questions and hypotheses are grouped into two large areas, (1) regulation of the general stress response mediated by the promoter specificity subunit RpoS; this is exemplary of a general stress response mechanism that affect transcription initiation, and (2) specific responses to DNA damage such as subpathways of nucleotide excision repair; these are exemplary of how the DNA damage response interfaces with transcription elongation, termination as well as replication. The principal questions that will be addressed by my research plan are: A. How are activating and inhibitory regulatory inputs integrated to tune the RpoS core pathway and globally reprogram transcription in response to an adverse environment? How does the ClpXP adaptor RssB and stress-specific ClpXP anti-adaptors tune the proteolysis of RpoS in a stress-specific manner? B. What are the mechanisms for preferential recruitment of the NER machinery to specific lesions, or to the template strand, directly read by RNA polymerase? How is the availability of early NER factors regulated by proteolysis in the context of DNA damage and transcription-coupled DNA repair? How and when do transcription-repair coupling factors collaborate with key players in the SOS response to promote mutagenesis? Can we leverage these mechanisms towards developing novel anti-evolution drugs for combination therapies against infection with diverse pathogens? Previous work has already allowed us to build a critical collection of reagents and expertise in the structural biology and biochemistry of transcription-coupled repair and RpoS biology. This gives us now an excellent entry point for a mechanistic dissection of the processes listed above and the development of novel antimicrobial strategies. The significance of our work is thus not only fundamental and conceptual in nature, but has immediate applications in controlling the worldwide public health crisis of antimicrobial resistance, particularly in the age of the COVID-19 pandemic.


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 = $392,500 )
2025	2025	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	005	4	5/23/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$661,147
2025	2025	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	002	4	4/30/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$392,500
2025	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	001	3	4/30/2025	NON-COMPETING CONTINUATION	$0
2025	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	004	3	5/23/2025	NON-COMPETING CONTINUATION	-$398,750
2025	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	000	3	11/6/2024	NON-COMPETING CONTINUATION	$0
2025	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	003	2	5/23/2025	NON-COMPETING CONTINUATION	-$262,397
														Subtotal = $392,500

Issue Date FY: 2024 ( Subtotal = $398,750 )
2024	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	001	3	6/28/2024	NON-COMPETING CONTINUATION	$39,875
2024	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	000	3	4/19/2024	NON-COMPETING CONTINUATION	$358,875
														Subtotal = $398,750

Issue Date FY: 2023 ( Subtotal = $398,750 )
2023	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	000	2	3/29/2023	NON-COMPETING CONTINUATION	$398,750
														Subtotal = $398,750

Issue Date FY: 2022 ( Subtotal = $398,438 )
2022	2022	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	000	1	2/11/2022	NEW	$398,438
														Subtotal = $398,438

Grand Total All Awards = $1,588,438

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MECHANISMS AND MACROMOLECULAR INTERACTIONS UNDERLYING CELLULAR RESPONSES TO STRESS SIGNALS

Award Number: R35GM144124

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: 04/01/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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