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PreprintCC BY-NCbioRxiv

DHX30 is a replication stress-responsive R-loop helicase that safeguards genome stability

  • E. R. Nedelcu
  • N. C. Yeo
  • H. Huber
  • A. B. Prusty
  • T. Q. Truong
  • N. D. P. Dang
  • S. Harder
  • J. Lederbauer
  • I. Lessel1
  • N. Ripin
  • C. Kiel
  • U. Fischer
2 more authors
  • H.-J. Kreienkamp
  • D. Lessel1
  1. 1University of Regensburg
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Abstract

R-loops are three-stranded nucleic acid structures formed primarily during transcription that can obstruct replication fork progression, leading to replication stress and genome instability. Although RNA helicases are increasingly implicated in R-loop metabolism, how individual helicases safeguard genome integrity remains incompletely understood. Here we identify DHX30, a neurodevelopmental disorder-associated DExH-box RNA helicase, as a replication stress-responsive regulator of R-loops. We show that DHX30 localizes to the nucleus in addition to its known cytoplasmic and mitochondrial pools, and that its nuclear abundance in-creases following aphidicolin or camptothecin treatment. DHX30 deficiency results in RNA:DNA hybrid accumulation in human cells and zebrafish, R-loop-dependent DNA double-strand breaks, micronucleus formation, reduced DNA synthesis, and altered expression of immediate-early stress genes under basal conditions and following replication perturbation. Biochemically, DHX30 binds branched nucleic acid structures and directly unwinds R-loop substrates containing a 3' single-stranded RNA overhang in an ATP- and polarity-dependent manner. Proteomic analyses place DHX30 within a nuclear network of RNA- and R-loop-associated factors, including the RNA helicase DHX9. These findings establish DHX30 as a conserved R-loop-resolving helicase that protects from R-loop-induced replication perturbations, contributes to transcriptional homeostasis, and maintains genome stability, thereby providing a mechanistic framework for understanding DHX30-associated neurodevelopmental disorders.

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Cite

BibTeXRIS
BibTeX
@misc{nedelcu2026dhx30,
  title = {{DHX30 is a replication stress-responsive R-loop helicase that safeguards genome stability}},
  author = {E. R. Nedelcu and N. C. Yeo and H. Huber and A. B. Prusty and T. Q. Truong and N. D. P. Dang and S. Harder and J. Lederbauer and I. Lessel and N. Ripin and C. Kiel and U. Fischer and H.-J. Kreienkamp and D. Lessel},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.25.761626},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.25.761626v1},
  note = {CC BY-NC},
}
RIS
TY  - UNPB
TI  - DHX30 is a replication stress-responsive R-loop helicase that safeguards genome stability
AU  - E. R. Nedelcu
AU  - N. C. Yeo
AU  - H. Huber
AU  - A. B. Prusty
AU  - T. Q. Truong
AU  - N. D. P. Dang
AU  - S. Harder
AU  - J. Lederbauer
AU  - I. Lessel
AU  - N. Ripin
AU  - C. Kiel
AU  - U. Fischer
AU  - H.-J. Kreienkamp
AU  - D. Lessel
PY  - 2026
DA  - 2026/10/25
PB  - bioRxiv
DO  - 10.64898/2026.10.25.761626
UR  - https://www.biorxiv.org/content/10.64898/2026.10.25.761626v1
AB  - R-loops are three-stranded nucleic acid structures formed primarily during transcription that can obstruct replication fork progression, leading to replication stress and genome instability. Although RNA helicases are increasingly implicated in R-loop metabolism, how individual helicases safeguard genome integrity remains incompletely understood. Here we identify DHX30, a neurodevelopmental disorder-associated DExH-box RNA helicase, as a replication stress-responsive regulator of R-loops. We show that DHX30 localizes to the nucleus in addition to its known cytoplasmic and mitochondrial pools, and that its nuclear abundance in-creases following aphidicolin or camptothecin treatment. DHX30 deficiency results in RNA:DNA hybrid accumulation in human cells and zebrafish, R-loop-dependent DNA double-strand breaks, micronucleus formation, reduced DNA synthesis, and altered expression of immediate-early stress genes under basal conditions and following replication perturbation. Biochemically, DHX30 binds branched nucleic acid structures and directly unwinds R-loop substrates containing a 3' single-stranded RNA overhang in an ATP- and polarity-dependent manner. Proteomic analyses place DHX30 within a nuclear network of RNA- and R-loop-associated factors, including the RNA helicase DHX9. These findings establish DHX30 as a conserved R-loop-resolving helicase that protects from R-loop-induced replication perturbations, contributes to transcriptional homeostasis, and maintains genome stability, thereby providing a mechanistic framework for understanding DHX30-associated neurodevelopmental disorders.
ER  -