Rnaseh2b-KO Mouse

Rnaseh2b, a component of the RNase H2 endonuclease complex, is crucial for ribonucleotide excision repair, removing ribonucleotides mis-incorporated into DNA. Mutations in this gene are associated with Aicardi-Goutières syndrome, an inflammatory disorder [2,3,4,6,8]. It is also involved in R-loop resolution, with implications for immune-related pathways as seen in ARID1A-deficient cancers where overexpression of RNASEH2B prevents cytosolic single-stranded DNA accumulation and IFN gene upregulation [5].

In prostate cancer, RNASEH2B loss can sensitize tumor cells to PARP inhibition. However, co-deletion of RB1, which is frequently co-located at chromosome 13q14 with RNASEH2B, overrides this sensitivity through E2F1-induced BRCA2 expression, enhancing homologous recombination repair. But loss of BRCA2 resensitizes these co-deleted cells to PARP inhibition [1,7]. In Aicardi-Goutières syndrome, RNASEH2B mutations lead to distinct clinical phenotypes compared to mutations in other related genes, with a relatively lower mortality rate among patients with RNASEH2B mutations compared to those with TREX1, RNASEH2A, and RNASEH2C mutations [6].

In conclusion, Rnaseh2b is essential for DNA repair and R-loop resolution, with its loss having significant implications in diseases like Aicardi-Goutières syndrome and prostate cancer. In prostate cancer, understanding the interaction between RNASEH2B and other genes like RB1 and BRCA2, as revealed by genetic studies, is crucial for determining the efficacy of PARP inhibitor-based therapies. In Aicardi-Goutières syndrome, RNASEH2B mutations contribute to a specific disease phenotype.

References:

1. Carmichael, Juliet, Figueiredo, Ines, Gurel, Bora, Sharp, Adam, de Bono, Johann. 2024. RNASEH2B loss and PARP inhibition in advanced prostate cancer. In The Journal of clinical investigation, 134, . doi:10.1172/JCI178278. https://pubmed.ncbi.nlm.nih.gov/38833311/

2. Crow, Yanick J, Chase, Diana S, Lowenstein Schmidt, Johanna, Orcesi, Simona, Rice, Gillian I. 2015. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. In American journal of medical genetics. Part A, 167A, 296-312. doi:10.1002/ajmg.a.36887. https://pubmed.ncbi.nlm.nih.gov/25604658/

3. Rice, Gillian I, Forte, Gabriella M A, Szynkiewicz, Marcin, Lebon, Pierre, Crow, Yanick J. 2013. Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study. In The Lancet. Neurology, 12, 1159-69. doi:10.1016/S1474-4422(13)70258-8. https://pubmed.ncbi.nlm.nih.gov/24183309/

4. Liu, Anran, Ying, Songcheng. 2023. Aicardi-Goutières syndrome: A monogenic type I interferonopathy. In Scandinavian journal of immunology, 98, e13314. doi:10.1111/sji.13314. https://pubmed.ncbi.nlm.nih.gov/37515439/

5. Maxwell, Matthew B, Hom-Tedla, Marianne S, Yi, Jawoon, Kaech, Susan M, Hargreaves, Diana C. 2024. ARID1A suppresses R-loop-mediated STING-type I interferon pathway activation of anti-tumor immunity. In Cell, 187, 3390-3408.e19. doi:10.1016/j.cell.2024.04.025. https://pubmed.ncbi.nlm.nih.gov/38754421/

6. Rice, Gillian, Patrick, Teresa, Parmar, Rekha, Lebon, Pierre, Crow, Yanick J. 2007. Clinical and molecular phenotype of Aicardi-Goutieres syndrome. In American journal of human genetics, 81, 713-25. doi:. https://pubmed.ncbi.nlm.nih.gov/17846997/

7. Miao, Chenkui, Tsujino, Takuya, Takai, Tomoaki, Kibel, Adam S, Jia, Li. 2022. RB1 loss overrides PARP inhibitor sensitivity driven by RNASEH2B loss in prostate cancer. In Science advances, 8, eabl9794. doi:10.1126/sciadv.abl9794. https://pubmed.ncbi.nlm.nih.gov/35179959/

8. Garau, Jessica, Masnada, Silvia, Dragoni, Francesca, Tonduti, Davide, Cereda, Cristina. 2021. Case Report: Novel Compound Heterozygous RNASEH2B Mutations Cause Aicardi-Goutières Syndrome. In Frontiers in immunology, 12, 672952. doi:10.3389/fimmu.2021.672952. https://pubmed.ncbi.nlm.nih.gov/33981319/