8-Oxoguanine transcriptional miscoding can transiently reproduce PAH-associated premature-stop transcripts
- 1Florida International University
Abstract
Pulmonary arterial hypertension (PAH) is associated with increased oxidative DNA damage, while haploinsufficiency of BMPR2 and other dosage-sensitive genes contributes directly to disease. Template-strand 8-oxoguanine (8-oxoG) provides a potential transient route to the same loss-of-function outcome through transcriptional mutagenesis without altering genomic DNA. RNA polymerase II can insert adenine opposite the lesion and generate a coding-sense C>A error in the nascent transcript. We asked whether this chemistry could generate premature-stop transcripts in dosage-sensitive PAH genes. Across 17,880 C>A-accessible coding positions in pulmonary vascular genes, 1,192 could generate premature termination codons, including 883 predicted to engage nonsense-mediated decay (NMD). Restricting these sites to expressed autosomal-dominant PAH genes with definitive ClinGen validity and established haploinsufficiency identified 116 NMD-prone positions in BMPR2, KDR, SMAD9, and TBX4. Eight exactly reproduce ClinVar pathogenic or likely pathogenic stop variants, including five in BMPR2. At BMPR2 c.1424, template-strand 8-oxoG and the expert-panel-reviewed genomic c.1424C>A allele is predicted to generate the same UAA-containing transcript. Published oxidized-guanine maps detect signal at seven of the eight coordinates, providing coordinate-level support for oxidative modification at these sites. These findings define a sequence-resolved route through which repairable oxidative DNA damage could transiently reproduce loss-of-function transcripts encoded by pathogenic PAH alleles without permanent genomic mutation.
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BibTeX
@misc{morenocaceres20268oxoguanine,
title = {{8-Oxoguanine transcriptional miscoding can transiently reproduce PAH-associated premature-stop transcripts}},
author = {S. Moreno-Caceres and A. M. Hayes and A. Delmas Eliason and D. P. Marciano},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.01.756055},
url = {https://www.biorxiv.org/content/10.64898/2026.10.01.756055v1},
note = {Public domain},
}
RIS
TY - UNPB
TI - 8-Oxoguanine transcriptional miscoding can transiently reproduce PAH-associated premature-stop transcripts
AU - S. Moreno-Caceres
AU - A. M. Hayes
AU - A. Delmas Eliason
AU - D. P. Marciano
PY - 2026
DA - 2026/10/01
PB - bioRxiv
DO - 10.64898/2026.10.01.756055
UR - https://www.biorxiv.org/content/10.64898/2026.10.01.756055v1
AB - Pulmonary arterial hypertension (PAH) is associated with increased oxidative DNA damage, while haploinsufficiency of BMPR2 and other dosage-sensitive genes contributes directly to disease. Template-strand 8-oxoguanine (8-oxoG) provides a potential transient route to the same loss-of-function outcome through transcriptional mutagenesis without altering genomic DNA. RNA polymerase II can insert adenine opposite the lesion and generate a coding-sense C>A error in the nascent transcript. We asked whether this chemistry could generate premature-stop transcripts in dosage-sensitive PAH genes. Across 17,880 C>A-accessible coding positions in pulmonary vascular genes, 1,192 could generate premature termination codons, including 883 predicted to engage nonsense-mediated decay (NMD). Restricting these sites to expressed autosomal-dominant PAH genes with definitive ClinGen validity and established haploinsufficiency identified 116 NMD-prone positions in BMPR2, KDR, SMAD9, and TBX4. Eight exactly reproduce ClinVar pathogenic or likely pathogenic stop variants, including five in BMPR2. At BMPR2 c.1424, template-strand 8-oxoG and the expert-panel-reviewed genomic c.1424C>A allele is predicted to generate the same UAA-containing transcript. Published oxidized-guanine maps detect signal at seven of the eight coordinates, providing coordinate-level support for oxidative modification at these sites. These findings define a sequence-resolved route through which repairable oxidative DNA damage could transiently reproduce loss-of-function transcripts encoded by pathogenic PAH alleles without permanent genomic mutation.
ER -