Final published version
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Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - Human RNase H2 upregulation counteracts oncogene- and chemotherapy-induced replication stress
AU - Wilkins, Rosanna J
AU - Kannan, Abirami
AU - Plass, Siobhan A
AU - Wilson, Claire
AU - Kelly, Richard D W
AU - Tang, Claire H M
AU - Kotsantis, Panagiotis
AU - Reijns, Martin A M
AU - Kanhere, Aditi
AU - Petermann, Eva
N1 - © 2025. The Author(s).
PY - 2025/7/10
Y1 - 2025/7/10
N2 - 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.
AB - 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.
U2 - 10.1038/s41388-025-03489-8
DO - 10.1038/s41388-025-03489-8
M3 - Journal article
C2 - 40640336
JO - Oncogene
JF - Oncogene
SN - 0950-9232
ER -