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Structural studies of function and regulation of microtubules and transcriptional gene expression machinery

Award Number: R35GM127018
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Our lab is dedicated to the mechanistic understanding of macromolecular function through the visualization of structure, dynamics, and regulatory interactions. Towards that goal, we use cryo-EM, together with biochemical and biophysical assays. Our areas of study are centered on the characterization of the regulatory molecular mechanisms governing the function of microtubules and of human transcription/epigenetic complexes. Microtubules (MTs) are essential polymers in eukaryotic cells built of ab-tubulin dimers. Dynamic instability, the switching between growing and shrinking phases due to the coupling of the assembly process to the exchange and hydrolysis of GTP in b-tubulin, is an essential property for MT function. Many MT cellular partners modulate MT dynamics or utilize it to carry out specific functions. In the last 5 years, we confirmed and complemented our past studies, which used non-hydrolyzable GTP analogs to characterize conformational changes in MTs that accompany GTP hydrolysis, now using of GTP-hydrolysis tubulin mutants. We also defined the mode of binding and action of cellular factors that regulate MT assembly, dynamics and organization in the cell and described the effect of tubulin acetylation on MT structure and function. We will continue this work with the central theme of adding complexity to our studies in order to bring us closer to the regulated function of microtubule cellular systems as we also add techniques complementary to our major tool, cryo-EM. Transcriptional regulation of gene expression is critical for growth and survival, and of obvious significance to human health. Its initiation involves RNA polymerase II (Pol II) together with TFIIA, TFIIB, TFIID, TFIIE, TFIIF, and TFIIH. Regulation is achieved by sequence-specific activators or repressors, co-factors, and chromatin remodeling/modifying complexes. During the last funding period we defined the structures of human TFIID and TFIIH, as well as other large transcriptional coactivators like the human SAGA, and the yeast NuA4 and RSC complexes. We will now characterize the human TIP60 complex, the binding of transcriptional co-activators to chromatin substrates, and pursue the dynamic visualization of TFIID engagement with promoter DNA to gain further knowledge of how these complexes work in the nucleus to regulate gene expression. Polycomb repressive complex 2 (PRC2) is an epigenetic gene silencer that methylates lysine 27 of histone H3 and is essential for cellular differentiation and development. After obtaining the structure of human PRC2 with its cofactors JARID2 and AEBP2 and its interaction with a di-nucleosome, we have now defined how PRC2 recognizes mono-ubiquitylated nucleosome, the substrate created by the other major Polycomb complex, PRC1. We will now further characterize the regulatory landscape of PRC2 looking into other histone modifications, different forms of PRC2 (i.e., other cofactors), the role of PRC2 auto-methylation, and binding of PRC2 to RNA


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 = $0 )
2025	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	7	11/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $617,187 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	003	7	9/19/2024	SUPPLEMENT FOR EXPANSION	$135,687
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	002	7	8/6/2024	NON-COMPETING CONTINUATION	$481,500
2024	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	001	6	7/16/2024	COMPETING CONTINUATION	$1
2024	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	5	7/16/2024	NON-COMPETING CONTINUATION	-$1
														Subtotal = $617,187

Issue Date FY: 2023 ( Subtotal = $470,807 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	001	6	8/10/2023	COMPETING CONTINUATION	$470,807
2023	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	5	8/4/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $470,807

Issue Date FY: 2022 ( Subtotal = $414,404 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	5	6/17/2022	NON-COMPETING CONTINUATION	$414,404
														Subtotal = $414,404

Issue Date FY: 2021 ( Subtotal = $414,404 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	4	4/29/2021	NON-COMPETING CONTINUATION	$414,404
														Subtotal = $414,404

Issue Date FY: 2020 ( Subtotal = $414,404 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	3	8/6/2020	NON-COMPETING CONTINUATION	$414,404
														Subtotal = $414,404

Issue Date FY: 2019 ( Subtotal = $645,758 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	001	2	7/30/2019	SUPPLEMENT FOR EXPANSION	$249,548
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	2	4/25/2019	NON-COMPETING CONTINUATION	$396,210
														Subtotal = $645,758

Issue Date FY: 2018 ( Subtotal = $196,081 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	2150 SHATTUCK AVE RM 313	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	000	1	4/27/2018	NEW	$196,081
														Subtotal = $196,081

Grand Total All Awards = $3,173,045

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Structural studies of function and regulation of microtubules and transcriptional gene expression machinery

Award Number: R35GM127018

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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