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Mechanisms of R-loop-Associated Genome Instability

Award Number: R01GM119334
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: 07/01/2016
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Mechanisms of R-loop-Associated Genome Instability - PROJECT SUMMARY Maintaining genome integrity is paramount for all cells, yet the essential cellular process of gene transcription introduces myriad opportunities for cells to incur damage to their genome. For example, transcription can lead to the formation of R-loops, three-stranded structures that contain an RNA-DNA hybrid and a region of single- stranded DNA. R-loops occur throughout the genome of mammalian cells and regulate various aspects of gene expression. They are typically dynamic, but some sequences and cellular perturbations can lead to stable R-loops that can stall transcription, block DNA replication, or cause DNA breaks via incompletely understood mechanisms. Moreover, some of these R-loops can be excised from the genome and accumulate in the cyto- plasm, where they can trigger innate immune responses and even cell death. Thus, cells carefully regulate R- loop formation and turnover. The long-term goal of this research program is to understand how cells identify deleterious R-loops (as dis- tinct from regulatory ones), how problematic R-loops are removed from the genome, and how these functions are disrupted in human diseases. Data suggest that stabilized R-loops become susceptible to processing (i.e., excision from the genome, followed by gap repair) when less mutagenic pathways such as unwinding of the RNA-DNA hybrid or degradation of the RNA component on the chromosome are unavailable or too slow. The objective of this application is to identify the pathway(s) that excises problematic R-loops from the genome and to define the sites and sequence characteristics of problematic R-loops. Aim 1 will investigate which DNA repair factors are involved in R-loop processing and determine how the nucleases that process these structures are recruited to the sites where R-loops are excised. Studies are also proposed to determine whether R-loop excision leaves a single-stranded gap in the DNA, to define the sites of nuclease processing and gap formation, and to identify the polymerases responsible for repairing these gaps. Aim 2 will characterize the genomic and sequence features of problematic R-loops and develop a novel, modu- lar experimental system to directly test hypotheses about the determinants of R-loop processing. These stud- ies will take advantage of new cell biological methods that have been developed to study R-loop processing and cutting-edge genomic approaches developed to map the spatial distribution of R-loops and R-loop pro- cessing products throughout the genome. Elucidating the features of problematic R-loops and how the cell copes with them has the potential to illumi- nate our understanding of how cells maintain genome stability and how this may go awry in cancer and other diseases states. This will lay a strong foundation for strategies to manipulate R-loop processing for therapeutic ends.


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 = $359,750 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	003	10	4/8/2025	NON-COMPETING CONTINUATION	$359,750
2025	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	002	9	2/19/2025	COMPETING CONTINUATION	$80,410
2025	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	8	2/19/2025	NON-COMPETING CONTINUATION	-$78,022
2025	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	8	2/19/2025	SUPPLEMENT FOR EXPANSION	-$2,388
														Subtotal = $359,750

Issue Date FY: 2024 ( Subtotal = $431,396 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	9	4/23/2024	COMPETING CONTINUATION	$431,396
														Subtotal = $431,396

Issue Date FY: 2023 ( Subtotal = $366,076 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	8	3/23/2023	NON-COMPETING CONTINUATION	$355,205
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	8	5/11/2023	SUPPLEMENT FOR EXPANSION	$10,871
														Subtotal = $366,076

Issue Date FY: 2022 ( Subtotal = $365,806 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	7	8/31/2022	SUPPLEMENT FOR EXPANSION	$10,601
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	7	4/22/2022	NON-COMPETING CONTINUATION	$355,205
														Subtotal = $365,806

Issue Date FY: 2021 ( Subtotal = $355,205 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	002	6	4/6/2021	NON-COMPETING CONTINUATION	$355,205
2021	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	5	4/5/2021	COMPETING CONTINUATION	$58,563
2021	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	4	4/5/2021	NON-COMPETING CONTINUATION	-$58,563
														Subtotal = $355,205

Issue Date FY: 2020 ( Subtotal = $370,775 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	5	6/30/2020	COMPETING CONTINUATION	$370,775
2020	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	4	6/22/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $370,775

Issue Date FY: 2019 ( Subtotal = $345,516 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	4	5/1/2019	NON-COMPETING CONTINUATION	$345,516
														Subtotal = $345,516

Issue Date FY: 2018 ( Subtotal = $355,502 )
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	3	4/24/2018	NON-COMPETING CONTINUATION	$355,502
														Subtotal = $355,502

Issue Date FY: 2017 ( Subtotal = $355,502 )
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	2	4/26/2017	NON-COMPETING CONTINUATION	$319,950
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	2	7/18/2017	NON-COMPETING CONTINUATION	$35,552
														Subtotal = $355,502

Issue Date FY: 2016 ( Subtotal = $355,502 )
2016	2016	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	1	6/23/2016	NEW	$355,502
														Subtotal = $355,502

Grand Total All Awards = $3,661,030

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Mechanisms of R-loop-Associated Genome Instability

Award Number: R01GM119334

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: 07/01/2016

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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