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The role of non-canonical nucleic acid structures in genome regulation

Award Number: R35GM161559
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: 04/01/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2031

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The role of non-canonical nucleic acid structures in genome regulation - Project Summary Nuclear processes such as transcription, replication, and repair disrupt the double stranded nature of DNA to result in the formation of non-canonical structures, the most prevalent being R-loops and G-quadruplexes (G4s). R-loops are three-stranded nucleic acid structures, which occur co-transcriptionally and comprise an RNA-DNA hybrid and a displaced single strand of DNA. The displaced ssDNA can form G4s if it contains spaced stretches of guanine nucleotides. G4 formation can facilitate the formation and stabilization of R-loops. Both R-loops and G4s have important roles in normal cellular function but are also deregulated in several developmental disorders and cancers. Our long-term goal is to elucidate how R-loops and G4 levels are managed in normal cells, how they regulate gene expression and genome organization, and how their misregulation contributes to various diseases. We discovered an enrichment for zinc finger domain containing proteins at R-loops and characterized one such factor, ADNP, to show that ADNP can resolve R-loops in vitro and that its loss results in accumulation of R-loops in vivo. We also identified a role for R-loops and G4s in genome organization by showing that these structures promote CTCF binding genome-wide, providing a new model for how transcription-induced R-loops can alter genome folding and contribute to lineage-specific gene expression programs during development. Through our work on another R-loop regulator, ATRX, we showed that while ATRX cannot resolve R-loops in vitro, its RNA binding activity can prevent R-loops from forming in vitro. In the next award cycle, we propose to build on these studies to: 1) identify a broader role for zinc finger proteins in genome organization through their interactions with R-loops and G4s; 2) determine the extent and mechanisms of ATRX-mediated R-loop regulation genome-wide and the impact on the localization of epigenetic regulators; and 3) elucidate the contribution of R- loops and G4s on the spatial organization of the genome.


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 = $363,191 )
2026	2026	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	1	3/16/2026	NEW	$363,191
														Subtotal = $363,191

Grand Total All Awards = $363,191

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The role of non-canonical nucleic acid structures in genome regulation

Award Number: R35GM161559

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: 04/01/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2031

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