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Deciphering fundamental biological processes involving protein-nucleic acid interactions at the molecular level

Award Number: R35GM130290
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: 01/01/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Deciphering fundamental biological processes involving protein-nucleic acid interactions at the molecular level - ABSTRACT The central goal of the Schumacher lab is to deduce molecular principles governing fundamental biological processes involving protein-nucleic acid interactions. These investigations focus on processes in microbes and intersect with the lab’s interests in microbial pathogenesis. Indeed, while the main goal is to elucidate biological mechanisms at the atomic level, these studies also provide potential targets for the development of urgently needed antimicrobial agents. Alarmingly, recent estimates suggest that deaths from antimicrobial resistance bacteria may exceed 10 million deaths worldwide by 2050 if steps are not taken to generate new treatments. The specific processes we investigate include transcription, DNA organization and RNA editing. Bacteria must be able to sense and respond to environmental changes for their survival and in some cases, proper development, so our studies on transcription focus on important networks and address how environmental cues are signaled and detected by transcription switches. Streptomyces bacteria represent the main source of antibacterial and other key drugs, which they generate concomitant with development. Thus, understanding their developmental lifecycle has been of significant interest for decades, although it is a mystery what drives this process. Our studies in the last few years have revealed that this developmental switch is controlled by the second messenger, c-di-GMP, functioning through two global transcription regulators, BldD and WhiG. These regulators control the first and second steps in Streptomyces development, respectively, but how c-di-GMP levels are sensed and signaled to these regulators are unknown and is a question we will address in this proposal. Initial studies unveiled a possible link between WhiG and a c-di-GMP phosphodiesterase, possibly indicating colocalization as a mechanism to control the second developmental step, which we will investigate. Studies will also be performed to analyze c-di-GMP levels and identify and characterize additional c-di-GMP modulated developmental regulators. Using a combination of cryo-EM, biochemistry and in vivo studies, we will also dissect the molecular mechanism by which nitrogen levels are sensed in Gram-positive bacteria by the novel Glutamine Synthetase-GlnR signaling pathway whereby the central enzyme for a metabolic pathway (GS) directly transduces nutrient availability to its master transcription regulator (GlnR). Finally, we will elucidate the signal and mechanism behind the first SOS-independent DNA repair pathway in bacteria. Another focus of the lab is the unusual RNA editing process in the mitochondria of kinetoplastid parasitic protozoans called kinetoplastid RNA (kRNA) editing. A recently identified accessory complex, the MRB1 complex, is required for this process. However, the structure and mechanisms of action of this complex are completely unknown. We will obtain structures of this complex and dissect its various molecular functions in editing. These combined studies will elucidate fundamental biological processes at the molecular level, leading to the discovery of potential chemotherapeutic targets against microbial 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: 2025 ( Subtotal = $582,976 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	003	8	12/17/2024	NON-COMPETING CONTINUATION	$582,976
2025	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	000	7	11/11/2024	NON-COMPETING CONTINUATION	$0
2025	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	002	6	12/10/2024	COMPETING CONTINUATION	$2,294
2025	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	001	5	12/10/2024	NON-COMPETING CONTINUATION	-$2,294
														Subtotal = $582,976

Issue Date FY: 2024 ( Subtotal = $886,751 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	000	7	11/30/2023	NON-COMPETING CONTINUATION	$582,976
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	001	7	6/25/2024	NON-COMPETING CONTINUATION	$64,775
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	002	7	7/17/2024	SUPPLEMENT FOR EXPANSION	$239,000
														Subtotal = $886,751

Issue Date FY: 2023 ( Subtotal = $656,315 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	003	6	8/31/2023	COMPETING CONTINUATION	$268,360
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	000	5	1/6/2023	NON-COMPETING CONTINUATION	$523,738
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	002	5	8/24/2023	NON-COMPETING CONTINUATION	-$193,975
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	001	5	3/31/2023	NON-COMPETING CONTINUATION	$58,192
														Subtotal = $656,315

Issue Date FY: 2022 ( Subtotal = $581,930 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	4	12/22/2021	NON-COMPETING CONTINUATION	$523,737
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	001	4	7/20/2022	NON-COMPETING CONTINUATION	$58,193
														Subtotal = $581,930

Issue Date FY: 2021 ( Subtotal = $581,930 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	001	3	3/10/2021	NON-COMPETING CONTINUATION	$58,193
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	3	12/17/2020	NON-COMPETING CONTINUATION	$523,737
														Subtotal = $581,930

Issue Date FY: 2020 ( Subtotal = $581,930 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	2	1/14/2020	NON-COMPETING CONTINUATION	$581,930
														Subtotal = $581,930

Issue Date FY: 2019 ( Subtotal = $316,002 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	1	12/27/2018	NEW	$316,002
														Subtotal = $316,002

Grand Total All Awards = $4,187,834

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Deciphering fundamental biological processes involving protein-nucleic acid interactions at the molecular level

Award Number: R35GM130290

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: 01/01/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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