Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

miR-19, a component of the oncogenic miR-17∼92 cluster, targets the DNA-end resection factor CtIP

Oncogene volume 34, pages 3977–3984 (2015)Cite this article

Subjects

Abstract

MicroRNA-19 (miR-19) was recently identified as the key oncogenic component of the polycistronic miR-17∼92 cluster, also known as oncomiR-1, which is frequently upregulated or amplified in multiple tumor types. However, the gene targets and the pathways underlying the tumor-promoting activity of miR-19 still remain largely elusive. CtIP/RBBP8 promotes DNA-end resection, a critical step in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR), and is considered to function as a tumor suppressor. In this study, we show that miR-19 downregulates CtIP expression by binding to two highly conserved sequences located in the 3′-untranslated region of CtIP mRNA. We further demonstrate that CtIP expression is repressed by miR-19 during continuous genotoxic stress in a p53-dependent manner. Finally, we report that miR-19 impairs CtIP-mediated DNA-end resection, which results in reduced HR levels and DNA damage hypersensitivity. By downregulating CtIP, miR-19 overexpression suppresses the faithful repair of DSBs that is crucial for genome maintenance. Our findings thus provide new mechanistic insight into the oncogenic role of the miR-17∼92 cluster.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Jackson SP, Bartek J . The DNA-damage response in human biology and disease. Nature 2009; 461: 1071–1078.

    Article  CAS  Google Scholar 

  2. Bunting SF, Nussenzweig A . End-joining, translocations and cancer. Nat Rev Cancer. 2013; 13: 443–454.

    Article  CAS  Google Scholar 

  3. Kakarougkas A, Jeggo PA . DNA DSB repair pathway choice: an orchestrated handover mechanism. Br J Radiol 2014; 87: 20130685.

    Article  CAS  Google Scholar 

  4. Jasin M, Rothstein R . Repair of strand breaks by homologous recombination. Cold Spring Harb Perspect Biol 2013; 5: a012740.

    Article  Google Scholar 

  5. Ferretti LP, Lafranchi L, Sartori AA . Controlling DNA-end resection: a new task for CDKs. Front Genet 2013; 4: 99.

    Article  Google Scholar 

  6. Wang H, Shi LZ, Wong CCL, Han X, Hwang PY-H, Truong LN et al. The Interaction of CtIP and Nbs1 connects CDK and ATM to regulate HR-Mediated Double-Strand Break Repair. PLoS Genet 2013; 9: e1003277.

    Article  CAS  Google Scholar 

  7. Steger Martin, Murina O, Hühn D, Ferretti LP, Walser R, Hänggi K et al. Prolyl isomerase PIN1 regulates DNA double-strand break repair by counteracting DNA end resection. Mol Cell 2013; 50: 333–343.

    Article  CAS  Google Scholar 

  8. You Z, Bailis JM . DNA damage and decisions: CtIP coordinates DNA repair and cell cycle checkpoints. Trends Cell Biol 2010; 20: 402–409.

    Article  CAS  Google Scholar 

  9. Chen P-L, Liu F, Cai S, Lin X, Li A, Chen Y et al. Inactivation of CtIP leads to early embryonic lethality mediated by G1 restraint and to tumorigenesis by haploid insufficiency. Mol Cell Biol 2005; 25: 3535–3542.

    Article  CAS  Google Scholar 

  10. Wang Y, Taniguchi T . MicroRNAs and DNA damage response: implications for cancer therapy. Cell Cycle 2013; 12: 32–42.

    Article  CAS  Google Scholar 

  11. Dimitrov SD, Lu D, Naetar N, Hu Y, Pathania S, Kanellopoulou C et al. Physiological modulation of endogenous BRCA1 p220 abundance suppresses DNA damage during the cell cycle. Genes Dev 2013; 27: 2274–2291.

    Article  CAS  Google Scholar 

  12. Wan G, Zhang X, Langley RR, Liu Y, Hu X, Han C et al. DNA-damage-induced nuclear export of precursor microRNAs is regulated by the ATM-AKT pathway. Cell Rep 2013; 3: 2100–2112.

    Article  CAS  Google Scholar 

  13. Chowdhury D, Choi YE, Brault ME . Charity begins at home: non-coding RNA functions in DNA repair. Nat Rev Mol Cell Biol 2013; 14: 181–189.

    Article  CAS  Google Scholar 

  14. Bartel DP . MicroRNAs: target recognition and regulatory functions. Cell 2009; 136: 215–233.

    Article  CAS  Google Scholar 

  15. Ameres SL, Zamore PD . Diversifying microRNA sequence and function. Nat Rev Mol Cell Biol 2013; 14: 475–488.

    Article  CAS  Google Scholar 

  16. Ling H, Fabbri M, Calin GA . MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov 2013; 12: 847–865.

    Article  CAS  Google Scholar 

  17. Olive V, Li Q, He L . mir-17∼92: a polycistronic oncomir with pleiotropic functions. Immunol Rev 2013; 253: 158–166.

    Article  Google Scholar 

  18. He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S et al. A microRNA polycistron as a potential human oncogene. Nature 2005; 435: 828–833.

    Article  CAS  Google Scholar 

  19. Mendell JT . miRiad roles for the miR-17∼92 cluster in development and disease. Cell 2008; 133: 217–222.

    Article  CAS  Google Scholar 

  20. Jin HY, Oda H, Lai M, Skalsky RL, Bethel K, Shepherd J et al. MicroRNA-17~92 plays a causative role in lymphomagenesis by coordinating multiple oncogenic pathways. EMBO J 2013; 32: 2377–2391.

    Article  CAS  Google Scholar 

  21. Grimson A, Farh KK-H, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP . MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell 2007; 27: 91–105.

    Article  CAS  Google Scholar 

  22. Mu P, Han Y-C, Betel D, Yao E, Squatrito M, Ogrodowski P et al. Genetic dissection of the miR-17~92 cluster of microRNAs in Myc-induced B-cell lymphomas. Genes Dev 2009; 23: 2806–2811.

    Article  CAS  Google Scholar 

  23. Olive V, Bennett MJ, Walker JC, Ma C, Jiang I, Cordon-Cardo C et al. miR-19 is a key oncogenic component of mir-17∼92. Genes Dev 2009; 23: 2839–2849.

    Article  CAS  Google Scholar 

  24. Mavrakis KJ, Wolfe AL, Oricchio E, Palomero T, de Keersmaecker K, McJunkin K et al. Genome-wide RNA-mediated interference screen identifies miR-19 targets in Notch-induced T-cell acute lymphoblastic leukaemia. Nat Cell Biol 2010; 12: 372–379.

    Article  CAS  Google Scholar 

  25. Farazi TA, Hoeve Ten JJ, Brown M, Mihailovic A, Horlings HM, van de Vijver MJ et al. Identification of distinct miRNA target regulation between breast cancer molecular subtypes using AGO2-PAR-CLIP and patient datasets. Genome Biol 2014; 15: R9.

    Article  Google Scholar 

  26. Hafner M, Landthaler M, Burger L, Khorshid M, Hausser J, Berninger P et al. Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell 2010; 141: 129–141.

    Article  CAS  Google Scholar 

  27. Betel D, Koppal A, Agius P, Sander C, Leslie C . Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites. Genome Biol 2010; 11: R90.

    Article  Google Scholar 

  28. Saetrom P, Heale BSE, Snøve O, Aagaard L, Alluin J, Rossi JJ . Distance constraints between microRNA target sites dictate efficacy and cooperativity. Nucleic Acids Res 2007; 35: 2333–2342.

    Article  CAS  Google Scholar 

  29. Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ . miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res 2006; 34: D140–D144.

    Article  CAS  Google Scholar 

  30. Landthaler M, Gaidatzis D, Rothballer A, Chen PY, Soll SJ, Dinic L et al. Molecular characterization of human Argonaute-containing ribonucleoprotein complexes and their bound target. RNA 2008; 14: 2580–2596.

    Article  CAS  Google Scholar 

  31. Mayr C, Bartel DP . Widespread shortening of 3′UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell 2009; 138: 673–684.

    Article  CAS  Google Scholar 

  32. Suzuki HI, Yamagata K, Sugimoto K, Iwamoto T, Kato S, Miyazono K . Modulation of microRNA processing by p53. Nature 2009; 460: 529–533.

    Article  CAS  Google Scholar 

  33. He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang Y et al. A microRNA component of the p53 tumour suppressor network. Nature 2007; 447: 1130–1134.

    Article  CAS  Google Scholar 

  34. Sartori AA, Lukas C, Coates J, Mistrik M, Fu S, Bartek J et al. Human CtIP promotes DNA end resection. Nature 2007; 450: 509–514.

    Article  CAS  Google Scholar 

  35. Kousholt AN, Fugger K, Hoffmann S, Larsen BD, Menzel T, Sartori AA et al. CtIP-dependent DNA resection is required for DNA damage checkpoint maintenance but not initiation. J Cell Biol 2012; 197: 869–876.

    Article  CAS  Google Scholar 

  36. Gravel S, Chapman JR, Magill C, Jackson SP . DNA helicases Sgs1 and BLM promote DNA double-strand break resection. Genes Dev 2008; 22: 2767–2772.

    Article  CAS  Google Scholar 

  37. Wu Q, Yang Z, An Y, Hu H, Yin J, Zhang P et al. MiR-19a/b modulate the metastasis of gastric cancer cells by targeting the tumour suppressor MXD1. Cell Death Dis 2014; 5: e1144.

    Article  CAS  Google Scholar 

  38. Castellano L, Giamas G, Jacob J, Coombes RC, Lucchesi W, Thiruchelvam P et al. The estrogen receptor-alpha-induced microRNA signature regulates itself and its transcriptional response. Proc Natl Acad Sci USA 2009; 106: 15732–15737.

    Article  CAS  Google Scholar 

  39. Hayashita Y, Osada H, Tatematsu Y, Yamada H, Yanagisawa K, Tomida S et al. A polycistronic microRNA cluster, miR-17∼92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res 2005; 65: 9628–9632.

    Article  CAS  Google Scholar 

  40. Pierce AJ, Johnson RD, Thompson LH, Jasin M . XRCC3 promotes homology-directed repair of DNA damage in mammalian cells. Genes Dev 1999; 13: 2633–2638.

    Article  CAS  Google Scholar 

  41. Bennardo N, Cheng A, Huang N, Stark JM . Alternative-NHEJ is a mechanistically distinct pathway of mammalian chromosome break repair. PLoS Genet 2008; 4: e1000110.

    Article  Google Scholar 

  42. Ebert MS, Sharp PA . Roles for microRNAs in conferring robustness to biological processes. Cell 2012; 149: 515–524.

    Article  CAS  Google Scholar 

  43. Martin NT, Nakamura K, Davies R, Nahas SA, Brown C, Tunuguntla R et al. ATM-dependent MiR-335 targets CtIP and modulates the DNA damage response. PLoS Genet 2013; 9: e1003505.

    Article  CAS  Google Scholar 

  44. Gunn A, Stark JM . I-SceI-based assays to examine distinct repair outcomes of mammalian chromosomal double strand breaks. Methods Mol Biol 2012; 920: 379–391.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are very grateful to M Menigatti, A Mueller and J Stark for providing reagents and cell lines. We wish to thank A Porro and J Jiricny for critical reading of the manuscript. This work was financially supported in part by grants of the Zurich Cancer League and the Sophien-Stiftung zur Förderung der klinischen Krebsforschung (to AAS). DH is supported by the Swiss Cancer League and AAS by the Vontobel-Stiftung.

Author information

Authors and Affiliations

  1. Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland

    D Hühn & A A Sartori

  2. Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen N, Denmark

    A N Kousholt & C S Sørensen

Authors
  1. D Hühn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A N Kousholt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C S Sørensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A A Sartori
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A A Sartori.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hühn, D., Kousholt, A., Sørensen, C. et al. miR-19, a component of the oncogenic miR-17∼92 cluster, targets the DNA-end resection factor CtIP. Oncogene 34, 3977–3984 (2015). https://doi.org/10.1038/onc.2014.329

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2014.329

This article is cited by

Search

Advanced search

Quick links