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Structural study of direct associations between cellular RNA polymerase and regulatory factors during the transcription cycle

Award Number: R35GM131860
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary The long-term goal of our research is to understand transcription mechanisms of cellular RNA polymerase. Our research has made major contributions to provide structures of RNA polymerase at the different stage of transcription cycle. During the next five years, we will continue to study the transcription machinery in bacteria and archaea to provide insights of the fundamental mechanism of transcription, which is conserved from bacteria to human. Over the last 20 years, X-ray crystallography has been playing a major role in the structural biology of RNA polymerase and revealed many important structures. RNA polymerases at evident stages in the mainstream of the transcription cycle are often referred to RNA polymerase core enzyme, holoenzymes, open complex with a strong promoter, transcription initiation and elongation complexes. These structures have been well characterized due to their stable natures. A challenge in the structural biology of cellular RNA polymerase is to visualize transient interactions of RNA polymerase with other regulatory factors and ligands that occur in between each evident stage in the mainstream or at the branched pathways from the mainstream of transcription cycle. Due to their elusive natures, crystallization of such macromolecular assemblies has been a bottleneck and thus limited the approach by X-ray crystallography. In the last couple of years, the resolution of macromolecular structures determined by cryo-electron microscopy (cryo-EM) has been drastically improved due to multiple technical advances, allowing us to visualize heterogenous and large assembly of macromolecular complexes. We will use structural biology methods including both cryo-EM and X-ray crystallography together with other biochemical approaches to visualize these transient interactions and investigate their effects for transcription process. Major targets of our study are: 1) the interaction between the Escherichia coli RNA polymerase and DksA/ppGpp for transcription regulation during the stringent response; 2) the interaction between bacterial RNA polymerase and ATP-dependent motor enzyme for rescuing stalled RNA polymerase at the end of transcription cycle; and 3) the interaction between archaeal RNA polymerase and ATP-dependent transcription termination factor Eta for disrupting a stalled transcription elongation complex to initiate the transcription-coupled DNA repair.


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: 2023 ( Subtotal = $525,501 )
2023	2023	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	5	8/14/2023	NON-COMPETING CONTINUATION	$387,999
2023	2023	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	001	5	8/16/2023	SUPPLEMENT FOR EXPANSION	$137,502
														Subtotal = $525,501

Issue Date FY: 2022 ( Subtotal = $387,999 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	4	4/12/2022	NON-COMPETING CONTINUATION	$349,196
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	001	4	7/22/2022	NON-COMPETING CONTINUATION	$38,803
														Subtotal = $387,999

Issue Date FY: 2021 ( Subtotal = $387,999 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	3	4/8/2021	NON-COMPETING CONTINUATION	$387,999
														Subtotal = $387,999

Issue Date FY: 2020 ( Subtotal = $470,164 )
2020	2020	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	001	2	7/16/2020	SUPPLEMENT FOR EXPANSION	$82,165
2020	2020	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	2	4/17/2020	NON-COMPETING CONTINUATION	$387,999
														Subtotal = $470,164

Issue Date FY: 2019 ( Subtotal = $423,543 )
2019	2019	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	1	7/1/2019	NEW	$420,584
2019	2019	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	001	1	7/9/2019	NEW	$2,959
														Subtotal = $423,543

Grand Total All Awards = $2,195,206

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Structural study of direct associations between cellular RNA polymerase and regulatory factors during the transcription cycle

Award Number: R35GM131860

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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