TOP1MT rs2293925 is an enhancer‐active regulatory SNP that shapes mitochondrial R‐loop dynamics

Abstract

Mitochondrial topoisomerase 1 (TOP1MT) regulates mitochondrial DNA (mtDNA) topology during transcription and replication. Perturbed mtDNA maintenance and RNA metabolism have been implicated in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Here we show that the common TOP1MT variant rs2293925 (R525W) has enhancer-like activity and is associated with increased mitochondrial R-loops (RNA : DNA hybrids). Tissue-dependent expression, quantitative trait locus analysis, chromatin-state annotation, reporter assays, and allele-specific DNA-protein binding assays support a transcriptional regulatory role for rs2293925. In isogenic cell models, rs2293925 increased TOP1MT mRNA and protein abundance, and this was accompanied by increased mitochondrial R-loop signal. TOP1MT trapping with lamellarin D supported increased TOP1MT-R525W occupancy at mitochondrial control region sites together with enhanced R-loops, consistent with altered TOP1MT-mtDNA interaction and/or increased TOP1MT abundance. Elevated mitochondrial R-loop signal was also detected in a pilot cohort of sporadic ALS samples carrying rs2293925 and in neural stem cells derived from C9orf72-positive ALS patients. These data support a dual-effect model in which rs2293925 increases TOP1MT expression and is associated with altered mitochondrial R-loop dynamics, linking common genetic variation to mitochondrial nucleic acid stress in disease-relevant contexts.

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BibTeX

@article{varga2026top1mt,
  title = {{TOP1MT rs2293925 is an enhancer‐active regulatory SNP that shapes mitochondrial R‐loop dynamics}},
  author = {Dóra Varga and Zsolt Ráduly and Beáta Boros-Oláh and Éva Nagy and Zsolt Karányi and László Halász and Bálint László Bálint and György Vámosi and Emese Tóth and Péter Bai and Serena Santangelo and Patrizia Bossolasco and Antonia Ratti and Vincent Géli and Yves Pommier and Lóránt Székvölgyi},
  journal = {FEBS Journal},
  year = {2026},
  month = jul,
  doi = {10.1111/febs.70649},
  url = {https://hal.science/hal-05855030v1},
  note = {CC BY-NC},
}

RIS

TY  - JOUR
TI  - TOP1MT rs2293925 is an enhancer‐active regulatory SNP that shapes mitochondrial R‐loop dynamics
AU  - Dóra Varga
AU  - Zsolt Ráduly
AU  - Beáta Boros-Oláh
AU  - Éva Nagy
AU  - Zsolt Karányi
AU  - László Halász
AU  - Bálint László Bálint
AU  - György Vámosi
AU  - Emese Tóth
AU  - Péter Bai
AU  - Serena Santangelo
AU  - Patrizia Bossolasco
AU  - Antonia Ratti
AU  - Vincent Géli
AU  - Yves Pommier
AU  - Lóránt Székvölgyi
PY  - 2026
DA  - 2026/07/08
JO  - FEBS Journal
DO  - 10.1111/febs.70649
UR  - https://hal.science/hal-05855030v1
AB  - Mitochondrial topoisomerase 1 (TOP1MT) regulates mitochondrial DNA (mtDNA) topology during transcription and replication. Perturbed mtDNA maintenance and RNA metabolism have been implicated in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Here we show that the common TOP1MT variant rs2293925 (R525W) has enhancer-like activity and is associated with increased mitochondrial R-loops (RNA : DNA hybrids). Tissue-dependent expression, quantitative trait locus analysis, chromatin-state annotation, reporter assays, and allele-specific DNA-protein binding assays support a transcriptional regulatory role for rs2293925. In isogenic cell models, rs2293925 increased TOP1MT mRNA and protein abundance, and this was accompanied by increased mitochondrial R-loop signal. TOP1MT trapping with lamellarin D supported increased TOP1MT-R525W occupancy at mitochondrial control region sites together with enhanced R-loops, consistent with altered TOP1MT-mtDNA interaction and/or increased TOP1MT abundance. Elevated mitochondrial R-loop signal was also detected in a pilot cohort of sporadic ALS samples carrying rs2293925 and in neural stem cells derived from C9orf72-positive ALS patients. These data support a dual-effect model in which rs2293925 increases TOP1MT expression and is associated with altered mitochondrial R-loop dynamics, linking common genetic variation to mitochondrial nucleic acid stress in disease-relevant contexts.
SN  - 1742-464X
SN  - 1742-4658
ER  -

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