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Mapping the DNA damage response in human cells with high-resolution functional genomics

Award Number: R35GM138167
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: 08/25/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Mapping the DNA damage response in human cells with high-resolution functional genomics - Project Summary DNA is the blueprint for life. It encodes the instructions for building and maintaining all organisms, from prokaryotes to humans. Despite this, DNA is frequently damaged. In fact, estimates suggest that each human cell may experience as many as ~105 lesions per day. To protect their genomes, organisms have therefore evolved a sophisticated set of mechanisms that sense, signal, and repair chemically diverse forms of DNA damage and, when damage cannot be repaired, induce programs of cell death. Decades of work have provided an extensive ‘parts list’ of these mechanisms in human cells. However, a major challenge to our understanding remains: We do not know how these mechanisms work together at the systems level to ensure response flexibility across conditions or enable compensation when one mechanism fails. This lack of systematic knowledge is problematic. It limits our comprehension of human diseases, such as cancers with DNA repair deficiencies, and it challenges our ability to develop and improve medical therapies that exploit response activities. We have recently developed functional genomics approaches that enable systematic interrogation of gene function in human cells, and with these tools, we propose to address this gap in knowledge. The fundamental logic behind our approaches is simple. We pair CRISPR-based genetic perturbation techniques with scalable methods for obtaining high-content phenotypes, such as single-cell RNA-sequencing. This allows us to collect data rich readouts of cell behavior across cells in which we have perturbed the function of many genes. With such data, we can infer functional relationships between genes and delineate genetic pathways. Here, I propose to use two of these technologies to map DNA damage response mechanisms in human cells, with the goals of improving genome editing technologies (Project 1) and achieving deeper understanding of drug responses during cancer therapy (Project 2). To enable the first project, we demonstrate a new approach that pairs CRISPR-based genetic screens with deep sequencing of DNA repair junctions to generate high-content readouts of DNA repair. We establish this approach using Cas9 from Streptococcus pyogenes and propose work that will serve as a roadmap for understanding genome editing technologies in the future.


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 = $451,000 )
2026	2026	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	6	2/20/2026	COMPETING CONTINUATION	$451,000
2026	2024	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	001	5	4/2/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $451,000

Issue Date FY: 2024 ( Subtotal = $399,697 )
2024	2024	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	5	7/23/2024	NON-COMPETING CONTINUATION	$399,697
														Subtotal = $399,697

Issue Date FY: 2023 ( Subtotal = $399,697 )
2023	2023	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	4	7/31/2023	NON-COMPETING CONTINUATION	$399,697
														Subtotal = $399,697

Issue Date FY: 2022 ( Subtotal = $399,697 )
2022	2022	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	3	6/29/2022	NON-COMPETING CONTINUATION	$399,697
														Subtotal = $399,697

Issue Date FY: 2021 ( Subtotal = $399,697 )
2021	2021	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	2	8/3/2021	NON-COMPETING CONTINUATION	$399,697
														Subtotal = $399,697

Issue Date FY: 2020 ( Subtotal = $399,697 )
2020	2020	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	1	8/21/2020	NEW	$399,697
														Subtotal = $399,697

Grand Total All Awards = $2,449,485

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Mapping the DNA damage response in human cells with high-resolution functional genomics

Award Number: R35GM138167

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: 08/25/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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