RNF25 Ubiquitin E3 activity Safeguards Genome Integrity by Modulating DNA Replication, Transcription and Translation.
- 1Andalusian Center for Molecular Biology and Regenerative Medicine, University of Seville
Abstract
The human genome encodes several hundreds of ubiquitin E3 enzymes, most of which have poorly understood biological roles. In search for novel ubiquitin E3 enzymes involved in DNA damage tolerance, we identified RNF25 as a candidate to have a role in DNA replication stress tolerance. Under stress conditions, RNF25 translocates to the nucleus in a cGAS-dependent manner, and loss of RNF25 ubiquitin E3 activity leads to the accumulation of replication-dependent ssDNA gaps. Combining functional assays with with mass-spectrometry based proteomics approaches such as TULIP2, iPOND-MS and TurboID, we found that, mechanistically, RNF25 promotes the stability of the replication fork at Transcription-Replication Conflicts by the ubiquitin-mediated clearance of RAD18, mono-ubiquitinated PCNA, H2B-K120ub and RECQL, among others. Lack of RNF25 ubiquitin E3 activity promotes the occurrence of Transcription-Replication Conflicts and destabilizes reversed replication forks, enabling re-priming and accumulation of ssDNA gaps behind the replication fork, ultimately compromising genome integrity. Overall, RNF25 regulates DNA replication, transcription and translation in an ubiquitin-based goldilocks.
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BibTeX
@misc{sotohidalgo2026rnf25,
title = {{RNF25 Ubiquitin E3 activity Safeguards Genome Integrity by Modulating DNA Replication, Transcription and Translation.}},
author = {E. Soto-Hidalgo and C. Espejo-Serrano and R. de Arellano and L. Gonzalez-Vinceiro and M. Marugan-Cardiel and I. Dominguez-Diaz and A. R. Hortal and M. L. Mateos-Martin and N. Garcia-Rodriguez and R. Freire and G. Millan-Zambrano and R. Gonzalez Prieto},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.21.753208},
url = {https://www.biorxiv.org/content/10.64898/2026.09.21.753208v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - RNF25 Ubiquitin E3 activity Safeguards Genome Integrity by Modulating DNA Replication, Transcription and Translation.
AU - E. Soto-Hidalgo
AU - C. Espejo-Serrano
AU - R. de Arellano
AU - L. Gonzalez-Vinceiro
AU - M. Marugan-Cardiel
AU - I. Dominguez-Diaz
AU - A. R. Hortal
AU - M. L. Mateos-Martin
AU - N. Garcia-Rodriguez
AU - R. Freire
AU - G. Millan-Zambrano
AU - R. Gonzalez Prieto
PY - 2026
DA - 2026/09/21
PB - bioRxiv
DO - 10.64898/2026.09.21.753208
UR - https://www.biorxiv.org/content/10.64898/2026.09.21.753208v1
AB - The human genome encodes several hundreds of ubiquitin E3 enzymes, most of which have poorly understood biological roles. In search for novel ubiquitin E3 enzymes involved in DNA damage tolerance, we identified RNF25 as a candidate to have a role in DNA replication stress tolerance. Under stress conditions, RNF25 translocates to the nucleus in a cGAS-dependent manner, and loss of RNF25 ubiquitin E3 activity leads to the accumulation of replication-dependent ssDNA gaps. Combining functional assays with with mass-spectrometry based proteomics approaches such as TULIP2, iPOND-MS and TurboID, we found that, mechanistically, RNF25 promotes the stability of the replication fork at Transcription-Replication Conflicts by the ubiquitin-mediated clearance of RAD18, mono-ubiquitinated PCNA, H2B-K120ub and RECQL, among others. Lack of RNF25 ubiquitin E3 activity promotes the occurrence of Transcription-Replication Conflicts and destabilizes reversed replication forks, enabling re-priming and accumulation of ssDNA gaps behind the replication fork, ultimately compromising genome integrity. Overall, RNF25 regulates DNA replication, transcription and translation in an ubiquitin-based goldilocks.
ER -