Topoisomerase 1-dependent R-loop deficiency drives accelerated replication and genomic instability

Dan Sarni, Sonia Barroso, Alon Shtrikman, Michal Irony-Tur Sinai, Yifat S. Oren, Andrés Aguilera, Batsheva Kerem*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

DNA replication is a complex process tightly regulated to ensure faithful genome duplication, and its perturbation leads to DNA damage and genomic instability. Replication stress is commonly associated with slow and stalled replication forks. Recently, accelerated replication has emerged as a non-canonical form of replication stress. However, the molecular basis underlying fork acceleration is largely unknown. Here, we show that mutated HRAS activation leads to increased topoisomerase 1 (TOP1) expression, causing aberrant replication fork acceleration and DNA damage by decreasing RNA-DNA hybrids or R-loops. In these cells, restoration of TOP1 expression or mild replication inhibition rescues the perturbed replication and reduces DNA damage. Furthermore, TOP1 or RNaseH1 overexpression induces accelerated replication and DNA damage, highlighting the importance of TOP1 equilibrium in regulating R-loop homeostasis to ensure faithful DNA replication and genome integrity. Altogether, our results dissect a mechanism of oncogene-induced DNA damage by aberrant replication fork acceleration.

Original languageAmerican English
Article number111397
JournalCell Reports
Volume40
Issue number13
DOIs
StatePublished - 27 Sep 2022

Bibliographical note

Publisher Copyright:
© 2022 The Author(s)

Keywords

  • CP: Molecular biology
  • DNA replication
  • R loops
  • genomic instability
  • oncogenes
  • replication stress
  • topoisomerase 1

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