# NIH grant: Uncovering complex single-stranded DNA structures in biology (1R35GM165563-01) — retained record

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[original source ↗](https://reporter.nih.gov/project-details/1R35GM165563-01)

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NIH grant 1R35GM165563-01: Uncovering complex single-stranded DNA structures in biology
Institute: {'code': 'GM', 'abbreviation': 'NIGMS', 'name': 'National Institute of General Medical Sciences', 'admin_org_id': '12500024', 'admin_funding_url': ''}. PI: Luiz Fernando  Moreira Passalacqua. Award: $386985.
Start: 2026-07-23T00:00:00.
The non-coding functions performed by nucleic acids depend on specific secondary and tertiary
structures. Single-stranded DNA (ssDNA)—not the canonical duplex with a complementary strand—can fold and
adopt complex structures, just like RNAs do. Compared to RNAs and proteins, complex DNA structures remain
greatly underdetermined and underexplored, resulting in a significant gap in our understanding of ssDNA
structure-function relationships. The presence of ssDNA is widespread in mammalian genomes, and
computational analysis suggests that these ssDNAs form structures at locations with an involvement in gene
regulation. Moreover, ssDNA viruses, a major component of the earth virome with biomedical, ecological, and
economical relevance, infect hosts from all domains of life. In both cases, ssDNAs can fold and adopt complex
structures; however, the interplay between their structures and their biological functions remains elusive.
Therefore, the five-year plan of this research program centers on uncovering the structure-function
relationships of ssDNA found in nature. We will start by developing methods to probe structured ssDNAs in
cells. Initially, we will pursue two biomedically relevant lines of investigation: First, we will investigate complex
ssDNA structures in the displaced strand of R-loops. R-loops, branched nucleic acid structures composed of an
RNA-DNA hybrid with a displaced DNA strand, play multifaceted roles in various biological processes, being
able to exert both beneficial and harmful influences on cellular health. Dysregulated R-loops are associated with
cancers, neurological disorders, and rare diseases. Thus, R-loops have been proposed as drug targets. R-loop
formation exposes the displaced strand of DNA, allowing it to fold and adopt structures. However, the impact of
these structures is still largely unknown. Our goal is to map complex ssDNA structures in the displaced strand
of R-loops in breast cancer cells, to define their impact on R-loop formation and stability, and to elucidate selected
3D structures. Second, we will investigate complex ssDNA structures in the parvovirus B-19 (B19V) genome.
B19V is a linear ssDNA virus with a genome of approximately 5,600 nucleotides. B19V causes the Fifth disease
in children. Despite being a mild disease, B19V infection in pregnant women is an important cause of fetal
morbidity. Currently, there is no treatment for B19V. The B19V genome is flanked by hairpins at both termini,
which are involved in genome replication. Beyond these hairpins, there is a gap in knowledge on the formation
of ssDNA structures within the B19V genome and how they could contribute to viral fitness. Our goal is to map
complex ssDNA structures formed by the B19V genome during initial infection and determine the 3D structure
of selected ssDNA elements. Our proposed research program fills a major gap in scientific knowledge about
complex ssDNA structures in biology and will shed light on their functions. Furthermore, the proposed research
could potentially launch a new field in biomedical research and the design of therapeutics, since these DNA
structures could be involved in biological processes and be targeted by small molecules or biologics.
```



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