Artículo
Topoisomerase 1-dependent R-loop deficiency drives accelerated replication and genomic instability
Autor/es | Sarni, Dan
Barroso Ceballos, Sonia Inés Shtrikman, Alon Irony-Tur Sinai, Michal Oren, Yifat S. Aguilera López, Andrés Kerem, Batsheva |
Departamento | Universidad de Sevilla. Departamento de Genética |
Fecha de publicación | 2022 |
Fecha de depósito | 2022-10-14 |
Publicado en |
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Resumen | 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 ... 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. |
Agencias financiadoras | Israel Science Foundation Israeli Centers of Research Excellence Ministerio de Ciencia e Innovación (MICIN). España European Research Council (ERC) |
Identificador del proyecto | 176/11
1284/18 2535/16 PID2019-104270GB-I00/BMC ERC2014 AdG669898 TARLOOP |
Cita | Sarni, D., Barroso Ceballos, S.I., Shtrikman, A., Irony-Tur Sinai, M., Oren, Y.S., Aguilera López, A. y Kerem, B. (2022). Topoisomerase 1-dependent R-loop deficiency drives accelerated replication and genomic instability. Cell Reports, 40 (13), 111397. https://doi.org/10.1016/j.celrep.2022.111397. |
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