RT Journal Article
T1 Topoisomerase 1-dependent R-loop deficiency drives accelerated replication and genomic instability.
A1 Sarni, Dan
A1 Barroso, Sonia
A1 Shtrikman, Alon
A1 Irony-Tur Sinai, Michal
A1 Oren, Yifat S
A1 Aguilera, Andrés
A1 Kerem, Batsheva
K1 CP: Molecular biology
K1 DNA replication
K1 R loops
K1 genomic instability
K1 oncogenes
K1 replication stress
K1 topoisomerase 1
AB 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.
YR 2022
FD 2022
LK http://hdl.handle.net/10668/22077
UL http://hdl.handle.net/10668/22077
LA en
DS RISalud
RD May 11, 2025