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The central roles of SRSF1 in early-stage spliceosome assembly

Award Number: R35GM147091
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: 08/08/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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The central roles of SRSF1 in early-stage spliceosome assembly - Project Summary: Alternative splicing processes over 95% of human mRNA and enables a single gene to encode distinct protein isoforms of different functions. Dysregulation of alternative splicing causes incorrect selection of exons and consequently various human diseases. Alternative exons are selected in early-stage spliceosome assembly. Due to our limited knowledge about early-stage spliceosome assembly, it is still challenging to develop therapies for diseases related to aberrant RNA splicing. Early-stage spliceosome assembly involves selection of exons and recruitment to the splicing sites of ribonucleoprotein complexes U1 and U2. These processes depend on the interplay of Ser/Arg-rich proteins (SR), U1-70K and U2AF-35. SR proteins are the key factors that coordinate all these events. The SR family consists of 12 members and shares Arg-Ser repetitive regions (RS) that are subjected to phosphorylation. In this proposal, we have selected the prototype of the family, SRSF1, as a model to investigate the central roles of SR proteins in spliceosome assembly. Mounting cellular studies have shown that SRSF1 promotes inclusion of exons by binding to exonic splicing enhancer RNA motifs, and phosphorylation of SRSF1 regulates not only the overall splicing pattern, but also the spliceosome assembly. Despite the progress in cellular studies, elucidating the mechanisms by which phosphorylation of SRSF1 regulates exon selection and spliceosome assembly is challenging due to low solubility of SR proteins, U1-70K and U2AF-35. Our lab has obtained all three of these proteins in the soluble full-length form. With this success, we have found that the SRSF1 RS region (a) displays RNA-binding preference and its phosphorylation inhibits RNA binding; (b) is essential for interaction with U1-70K and U2AF-35, which are responsible for recruitment of U1 and U2 complexes, respectively; (c) mediates phase separation, which is consistent with its role in organizing nuclear speckles. This proposal will (1) use the high- throughput method RNA Bind-n-Seq to systematically investigate how phosphorylation regulates RNA-binding specificity of SRSF1; (2) use a combination of NMR, molecular dynamic simulations and other biophysical methods to elucidate the structural mechanism by which SRSF1 interacts with U1-70K and U2AF-35; (3) investigate how the RS region balance its roles in modulating RNA-binding affinity, mediating protein interactions, and organizing phase separation in the phase-separated state. In summary, our proposal will advance our knowledge of exon selection and splicing factor interaction during early-stage spliceosome assembly.


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 = $371,250 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Biomedical Research and Research Training	000	4	7/16/2025	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2024 ( Subtotal = $371,250 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Biomedical Research and Research Training	000	3	7/3/2024	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2023 ( Subtotal = $507,345 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Biomedical Research and Research Training	001	2	8/1/2023	SUPPLEMENT FOR EXPANSION	$136,095
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Biomedical Research and Research Training	000	2	7/26/2023	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $507,345

Issue Date FY: 2022 ( Subtotal = $371,250 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Biomedical Research and Research Training	000	1	8/7/2022	NEW	$371,250
														Subtotal = $371,250

Grand Total All Awards = $1,621,095

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The central roles of SRSF1 in early-stage spliceosome assembly

Award Number: R35GM147091

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: 08/08/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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