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Human RNase H2 upregulation counteracts oncogene- and chemotherapy-induced replication stress
Wilkins, Rosanna J. Kannan, Abirami Plass, Siobhan A. Wilson, Claire Kelly, Richard D. W. Tang, Claire H. M. Kotsantis, Panagiotis Reijns, Martin A. .M Kanhere, Aditi Petermann, Eva
Wilkins, Rosanna J.
Kannan, Abirami
Plass, Siobhan A.
Wilson, Claire
Kelly, Richard D. W.
Tang, Claire H. M.
Kotsantis, Panagiotis
Reijns, Martin A. .M
Kanhere, Aditi
Petermann, Eva
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Publication Date
2025-07-10
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Abstract
RNase H2 is a heterotrimeric endoribonuclease that resolves RNA:DNA hybrids and genome-embedded ribonucleotides, which are implicated in DNA replication stress and cancer development. Protein and/or mRNA levels of individual RNase H2 subunits are elevated in some cancers, but little is known about the mechanisms or consequences of RNase H2 upregulation. We report that RNase H2 subunits are upregulated at the protein level in response to replication stress induced by oncogenes and chemotherapy drugs in human cancer and non-cancer cell lines. We show that inducible overexpression of the RNASEH2B subunit increases levels of the active RNase H2 heterotrimer. While causing only subtle changes to gene expression, RNASEH2B overexpression is unexpectedly associated with increased RNA:DNA hybrid levels. RNASEH2B overexpression prevents further increases in RNA:DNA hybrid levels by camptothecin or hydroxyurea and reduces replication fork stalling in presence of these drugs. Surprisingly, RNase H2 levels do not strongly impact survival of chemotherapy treatments but appear to have more subtle effects on genome instability and innate immune signalling. In contrast, increased RNase H2 levels in presence of oncogenic HRAS limit not only RAS-induced replication fork stalling but also cell death. Our findings shed new light on the functions of RNase H2 and suggest that upregulation of RNase H2 may be an important aspect of replication stress responses in cancer.
Citation
Wilkins, R. J., Kannan, A., Plass, S. A., Wilson, C., Kelly, R. D. W., Tang, C. H. M., Kotsantis, P., Reijns, M. A. M., Kanhere, A., & Petermann, E. (2025). Human RNase H2 upregulation counteracts oncogene- and chemotherapy-induced replication stress. Oncogene, 44(35), 3255–3271. https://doi.org/10.1038/s41388-025-03489-8
Publisher
Springer Nature
Journal
Oncogene
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PubMed Central ID
Type
Article
Language
en
Description
The version of record of this article, first published in [Oncogene], is available online at Publisher’s website: http://dx.doi.org/10.1038/s41388-025-03489-8
Series/Report no.
ISSN
0950-9232
EISSN
1476-5594
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Sponsors
Cancer Research UK Programme Foundation (C25526/A28275). Worldwide Cancer Research grant (13-1048). UK Medical Research Council (MRC) Human Genetics Unit grant (MC_UU_00035/10).