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
Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, UK.
Birmingham Centre for Genome Biology, University of Birmingham, Birmingham, UK.
Oncogene. 2025 Jul 10. doi: 10.1038/s41388-025-03489-8.
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.
核糖核酸酶H2（RNase H2）是一种异源三聚体内切核糖核酸酶，可降解RNA:DNA杂交体和基因组嵌入的核糖核苷酸，这些物质与DNA复制应激和癌症发展有关。在某些癌症中，单个RNase H2亚基的蛋白质和/或mRNA水平会升高，但对于RNase H2上调的机制或后果知之甚少。我们报告称，在人类癌症和非癌细胞系中，响应癌基因和化疗药物诱导的复制应激，RNase H2亚基在蛋白质水平上被上调。我们表明，RNASEH2B亚基的可诱导过表达会增加活性RNase H2异源三聚体的水平。虽然RNASEH2B过表达仅对基因表达产生细微变化，但出乎意料的是，它与RNA:DNA杂交体水平的增加有关。RNASEH2B过表达可防止喜树碱或羟基脲导致的RNA:DNA杂交体水平进一步升高，并在这些药物存在的情况下减少复制叉停滞。令人惊讶的是，RNase H2水平对化疗治疗的存活率影响不大，但似乎对基因组不稳定性和先天免疫信号传导有更细微的影响。相比之下，在致癌性HRAS存在的情况下，RNase H2水平的升高不仅限制了RAS诱导的复制叉停滞，还限制了细胞死亡。我们的研究结果为RNase H2的功能提供了新的见解，并表明RNase H2的上调可能是癌症中复制应激反应的一个重要方面。
