{
  "id": 12931069,
  "title": "8-Oxoguanine transcriptional miscoding can transiently reproduce PAH-associated premature-stop transcripts",
  "url": "https://urgent.news/2026/10/08/8-oxoguanine-transcriptional-miscoding-can-transiently-reproduce-pah",
  "topic": "science",
  "section": "Science",
  "published": "2026-10-08T00:00:00.000Z",
  "source": {
    "name": "bioRxiv",
    "slug": "biorxiv",
    "url": "https://www.biorxiv.org/content/10.64898/2026.10.01.756055v1?rss=1"
  },
  "original_language": "en",
  "account": "Pulmonary arterial hypertension (PAH) can be linked to heightened oxidative DNA damage, which occurs due to haploinsufficiency of BMPR2 and other dosage-sensitive genes. Instead of directly modifying genomic DNA, 8-oxoguanine (8-oxoG) serves as a potential temporary pathway for inducing loss-of-function transcripts in PAH-associated genes. RNA polymerase II introduces adenine in the presence of the lesion, resulting in a coding-sense C A error within the newly synthesized transcript. The inquiry focused on whether this process could generate premature-stop transcripts in crucial PAH genes. Out of 17,880 accessible coding positions in pulmonary vascular genes, 1,192 were identified as potential sites for generating premature termination codons, out of which 883 were predicted to trigger nonsense-mediated decay (NMD). By narrowing down to expressed autosomal-dominant PAH genes with confirmed ClinGen validity and known haploinsufficiency, 116 NMD-prone positions were found within BMPR2, KDR, SMAD9, and TBX4. Eight of these sites perfectly match ClinVar pathogenic or likely pathogenic stop variants, including five in BMPR2. At BMPR2 c.1424, the template-strand 8-oxoG and the expert-panel-reviewed genomic c.1424C A allele are predicted to produce the same UAA-containing transcript. Published oxidized-guanine maps validate signals at seven of the eight coordinates, offering direct evidence of oxidative modification at these sites. These findings illustrate a precise sequence-based mechanism through which repairable oxidative DNA damage can transiently replicate loss-of-function transcripts generated by pathogenic PAH alleles, without causing lasting genomic mutations.",
  "summary": "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…",
  "key_points": [],
  "editors_take": null,
  "illustration": null,
  "coverage": {
    "outlets": 1,
    "also_reported_by": []
  },
  "ai_generated": true,
  "disclaimer": "Summaries, key points and the editor’s take are written by software from other outlets’ reporting and may contain errors — always check the linked original."
}