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DNA Damage & DNA Replication: a Complex Relationship

Award Number: R35GM136278
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: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2030

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DNA Damage & DNA Replication: a Complex Relationship - Our overarching goals are: i. to define the mechanism(s) of ATM activation by the Mre11 complex; ii. to define the role(s) of the Mre11 complex in DNA replication; iii. To define the role(s) of the Mre11 complex and RTEL1 in response to DNA replication stress. As noted, our focus includes RTEL1 which acts to mitigate replication stress at the telomere. A combination of yeast and mouse genetics, biochemistry, and structural biology are employed to address these issues. Our previous work on these topics led to substantial scientific progress and insight regarding processes relevant to human health. Specific areas of inquiry are: · Genetic screens in yeast and mining of cancer genomic data revealed separation of function Rad50 mutations that affect ATM dependent DNA damage signaling without affecting the DNA repair functions of the Mre11 complex. These mutations constitute a resource for deciphering the mechanism by which the Mre11 complex activates the ATM kinase to initiate DNA damage signaling. · We have obtained a cryoEM structure of the S. cerevisiae MR complex. Ongoing structural analyses of rad50S mutants offer a unique opportunity to address the mechanism of Tel1/ATM activation by the Mre11 complex. · We have identified factors that function at the DNA replication fork in a manner that depends on the Mre11 complex. Those data reveal a link between innate immune signaling and genome integrity. An important focus of our laboratory is to understand the functional role(s) of those factors. Defects in factors that promote accurate DNA replication are highly correlated with human disease, and so understanding this fundamental process is an important priority in our work. · We developed a mammary organoid system examine the role of the Mre11 complex in suppressing breast cancer. Those studies provided compelling evidence that genomic instability activates a chronic interferon stimulated gene transcriptional program is driven by a nuclear innate immune DNA sensor. The attendant chromatin alterations dramatically increase the risk of oncogene induce cancer. This forges a novel link between innate immune signaling and tumorigenesis. · Whereas the Mre11 complex functions at the replication fork, RTEL1 is a helicase that promotes accurate replication of telomeric DNA. We have discovered that RTEL1 influences the abundance and disposition of a long non coding RNA, called TERRA, that is transcribed from the subtelomeric regions of all eukaryotes. We also have preliminary data supporting the view that RTEL1 is a ubiquitin E3 ligase. Our goal in this aspect of our work is to understand the role of RTEL1 in maintaining telomere stability and mitigating telomeric DNA replication stress.


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 = $972,560 )
2026	2026	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	000	6	2/20/2026	COMPETING CONTINUATION	$972,560
														Subtotal = $972,560

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	000	5	11/4/2024	NON-COMPETING CONTINUATION	$0
2025	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	001	5	7/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $949,600 )
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	000	5	8/14/2024	NON-COMPETING CONTINUATION	$949,600
														Subtotal = $949,600

Issue Date FY: 2023 ( Subtotal = $1,043,034 )
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	000	3	6/27/2023	SUPPLEMENT FOR EXPANSION	$93,434
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	001	4	8/29/2023	NON-COMPETING CONTINUATION	$949,600
														Subtotal = $1,043,034

Issue Date FY: 2022 ( Subtotal = $949,600 )
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	000	3	7/1/2022	NON-COMPETING CONTINUATION	$949,600
														Subtotal = $949,600

Issue Date FY: 2021 ( Subtotal = $949,600 )
2021	2021	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	000	2	7/10/2021	NON-COMPETING CONTINUATION	$949,600
														Subtotal = $949,600

Issue Date FY: 2020 ( Subtotal = $654,008 )
2020	2020	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	000	1	7/21/2020	NEW	$654,008
														Subtotal = $654,008

Grand Total All Awards = $5,518,402

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DNA Damage & DNA Replication: a Complex Relationship

Award Number: R35GM136278

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: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2030

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