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Crosstalk between DNA repair pathways in repeat instability

Award Number: R01GM144553
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: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Crosstalk between DNA repair pathways in repeat instability - Project Summary/Abstract Approximately half the human genome is comprised of repetitive DNA sequences that are thought to control a wide range of cellular functions. DNA repeats are found throughout the genome, and are polymorphic in length due to their genetic instability. Mutation rates of repeat elements are 101-105 fold higher than in other parts of the genome, and is triggered by the formation of transient unusual DNA structures (extrahelical extrusions) during DNA metabolic processes. The detrimental consequences of repeat instability are exemplified by triplet repeat expansions that cause a number of neurodegenerative diseases such as Huntington’s disease, Friedreich’s ataxia and Fragile X related disorders. The rate of expansion of triplet repeats is proportional to repeat length and sequence homogeneity. DNA repair mechanisms have evolved to maintain genomic stability, and protect the DNA from damage caused by environmental agents. One such process is DNA mismatch repair (MMR), a highly conserved antimutagenic pathway that maintains the stability of the human genome by correcting replication errors and preventing chromosomal rearrangements. Unexpectedly, a mutagenic non- canonical function of MMR has been implicated as the cause of triplet repeat expansions. Loss of MMR function attenuates triplet repeat expansion, although the molecular mechanisms of this non-canonical MMR activity are poorly understood. However, this mutagenic action of MMR requires the proteins MutSb and MutLa (and possibly MutLg). FAN1 is a deoxyribonuclease that was originally identified as a factor involved in the repair of DNA interstrand crosslinks. Loss of FAN1 function exacerbates repeat expansion, suggesting a role for FAN1 in suppression of triplet repeat expansion by mechanisms that are not understood. We are interested in the molecular mechanisms responsible for the crosstalk between these opposing effects of MMR and FAN1 in the control of mutation production within triplet repeats. We have discovered a novel activator of the FAN1 nuclease on triplet repeat extrusions, a finding that represents the first step not only in our understanding of the mechanism of FAN1 action, but also in our quest to develop a unified understanding of the mechanism of triplet repeat expansion by integrating biochemical, cellular, and genetic studies. In Aim 1, we will elucidate the molecular features of FAN1 nuclease function by evaluating the modulatory effects of DNA sequence/structure and protein co-factors. In Aim 2, we will dissect the role of protein-DNA and protein-protein interactions in the repair of triplet repeat extrusions by FAN1. In Aim 3, we will use unbiased proteomic approaches to identify co-factors that facilitate FAN1 nuclease function in a cellular milieu. Completion of these studies will shed light on the pathways that modulate triplet repeat expansion, and will have implications more broadly for the mechanisms of genome instability.


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 = $280,800 )
2025	2025	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	000	3	12/9/2024	NON-COMPETING CONTINUATION	$280,800
														Subtotal = $280,800

Issue Date FY: 2024 ( Subtotal = $451,966 )
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	000	2	12/12/2023	NON-COMPETING CONTINUATION	$280,800
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	002	2	7/23/2024	NON-COMPETING CONTINUATION	$31,200
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	001	2	6/6/2024	SUPPLEMENT FOR EXPANSION	$139,966
														Subtotal = $451,966

Issue Date FY: 2023 ( Subtotal = $312,000 )
2023	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	000	1	1/23/2023	NEW	$312,000
														Subtotal = $312,000

Grand Total All Awards = $1,044,766

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Crosstalk between DNA repair pathways in repeat instability

Award Number: R01GM144553

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: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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