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Cyclin-dependent kinase control of cell-division and transcription cycles

Award Number: R35GM127289
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: 04/01/2018
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Cyclin-dependent kinase control of cell-division and transcription cycles - Project Summary RNA polymerase II (RNAPII), which catalyzes mRNA synthesis, is co-regulated by cyclin-dependent kinases (CDKs) and phosphatases to control transcription cycle progression and ensure coupling of elongation and processing. Derangements of the RNAPII cycle underlie cancer and other diseases; CDKs and phosphatases are potential drug targets, but how they collaborate to regulate gene expression is largely unknown. We seek to determine how specific phosphorylations are placed and removed in precise order to execute transitions between phases of transcription. In the past five years we uncovered two CDK-phosphatase switches that regulate RNAPII elongation. Our goals for the next five years are to understand how these circuits work to coordinate the transcription cycle, and how they might be disrupted with small molecules. Dissecting CDK-PPP switches: We identified two members of the phosphoprotein phosphatase (PPP) family as targets of inhibitory phosphorylation by Cdk9 (P-TEFb). PP4 and PP1 dephosphorylate the Cdk9 substrate Spt5 to regulate the onset and end of rapid elongation, respectively. To define roles of Cdk9-PPP crosstalk in transcription, we will introduce mutations that lock PP4 or PP1 in constitutively active (unphosphorylated) or inactive (phosphorylated) states and analyze genome-wide effects on RNAPII dynamics and gene expression. Unraveling control of RNAPII elongation by PPP family phosphatases: PP4 and the related PP2A, another phosphatase recruited to transcription complexes, dephosphorylate Spt5 with similar site specificity, and may cooperate to regulate RNAPII release from the promoter-proximal pause. We plan integrated genomic analyses to ask whether PP4 and PP2A work independently, in combination, or in response to different signals. Understanding how phosphorylation events are ordered in the RNAPII cycle: By analogy with the cell division cycle—also regulated by CDKs—the order of phosphorylations during transcription is likely determined by substrate specificities of CDKs and phosphatases, and by structural features of the substrates themselves. We will test this hypothesis for Cdk9, which has scores of substrates and is active throughout elongation. Functional dissection of a conserved elongation regulator: Spt5, large subunit of the conserved elongation factor DSIF, is the linchpin of elongation control by Cdk9-PPP switches; phosphorylations placed by Cdk9 at different sites in Spt5 are removed at different times by PP4 or PP1 and are likely to perform different functions in the transcription cycle. We will take a genome editing approach in human cells to dissect the functions of distinct Spt5 phosphorylations, and to elucidate their differential regulation by CDKs and phosphatases. Illuminating a link between transcription and cell cycle control: One CDK is a core component of both cell-division and transcriptional machineries: the TFIIH-associated Cdk7. As human cells re-enter the division cycle from quiescence, chromatin-bound Cdk7 is activated, potentially enhancing its function in G1-specific gene transcription. We will test this model and identify pathways that lead to Cdk7 activation at cell cycle entry.


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 = $507,000 )
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	001	9	3/18/2026	NON-COMPETING CONTINUATION	$50,700
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	9	1/30/2026	NON-COMPETING CONTINUATION	$456,300
														Subtotal = $507,000

Issue Date FY: 2025 ( Subtotal = $507,000 )
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	002	8	8/14/2025	NON-COMPETING CONTINUATION	$50,700
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	001	8	2/20/2025	NON-COMPETING CONTINUATION	$456,300
2025	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	7	11/13/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $507,000

Issue Date FY: 2024 ( Subtotal = $514,563 )
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	002	7	6/25/2024	NON-COMPETING CONTINUATION	$50,700
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	7	2/14/2024	NON-COMPETING CONTINUATION	$456,300
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	003	7	8/26/2024	SUPPLEMENT FOR EXPANSION	$7,563
2024	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	001	5	2/14/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $514,563

Issue Date FY: 2023 ( Subtotal = $507,000 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	6	2/23/2023	COMPETING CONTINUATION	$507,000
														Subtotal = $507,000

Issue Date FY: 2022 ( Subtotal = $464,704 )
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	001	5	7/20/2022	NON-COMPETING CONTINUATION	$46,474
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	5	3/31/2022	NON-COMPETING CONTINUATION	$418,230
														Subtotal = $464,704

Issue Date FY: 2021 ( Subtotal = $472,036 )
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	001	4	5/22/2021	SUPPLEMENT FOR EXPANSION	$7,332
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	4	3/25/2021	NON-COMPETING CONTINUATION	$464,704
														Subtotal = $472,036

Issue Date FY: 2020 ( Subtotal = $464,704 )
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	3	3/19/2020	NON-COMPETING CONTINUATION	$464,704
														Subtotal = $464,704

Issue Date FY: 2019 ( Subtotal = $464,704 )
2019	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	2	3/29/2019	NON-COMPETING CONTINUATION	$464,704
														Subtotal = $464,704

Issue Date FY: 2018 ( Subtotal = $464,704 )
2018	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	1	3/22/2018	NEW	$464,704
														Subtotal = $464,704

Grand Total All Awards = $4,366,415

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Cyclin-dependent kinase control of cell-division and transcription cycles

Award Number: R35GM127289

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: 04/01/2018

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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