Transformer2 proteins protect breast cancer cells from accumulating replication stress by ensuring productive splicing of checkpoint kinase 1

  • Andrew Best
  • Katherine James
  • Gerald Hysenaj
  • Alison Tyson-Capper
  • David J. Elliott
Review Article


Increased expression levels of the RNA splicing regulator Transformer2β (abbreviated Tra2β) have been reported in several types of cancer. Recent work has revealed an intimate cross-regulation between Tra2β and the highly similar Tra2α protein in human breast cancer cells, though these two proteins are encoded by separate genes created by a gene duplication that occurred over 500 million years ago. This cross-regulation involves splicing control of a special class of exons, called poison exons. Down-regulation of Tra2β reduces splicing inclusion of a poison exon in the mRNA encoding Tra2α, thereby up-regulating Tra2α protein expression. This buffers any splicing changes that might be caused by individual depletion of Tra2β alone. Discovery of this cross-regulation pathway, and its by-pass by joint depletion of both human Tra2 proteins, revealed Tra2 proteins are essential for breast cancer cell viability, and led to the identification of important targets for splicing control. These exons include a critical exon within the checkpoint kinase 1 (CHK1) gene that plays a crucial function in the protection of cancer cells from replication stress. Breast cancer cells depleted for Tra2 proteins have reduced CHK1 protein levels and accumulate DNA damage. These data suggest Tra2 proteins and/or their splicing targets as possible cancer drug targets.


RNA splicing gene expression breast cancer DNA damage CHK1 


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  1. 1.
    Eccles S A, Aboagye E O, Ali S, Anderson A S, Armes J, Berditchevski F, Blaydes J P, Brennan K, Brown N J, Bryant H E, Bundred N J, Burchell J M, Campbell A M, Carroll J S, Clarke R B, Coles C E, Cook G J, Cox A, Curtin N J, Dekker L V, Silva Idos S, Duffy S W, Easton D F, Eccles D M, Edwards D R, Edwards J, Evans D, Fenlon D F, Flanagan J M, Foster C, Gallagher W M, Garcia-Closas M, Gee J M, Gescher A J, Goh V, Groves A M, Harvey A J, Harvie M, Hennessy B T, Hiscox S, Holen I, Howell S J, Howell A, Hubbard G, Hulbert-Williams N, HunterMS, Jasani B, Jones L J, Key T J, Kirwan C C, Kong A, Kunkler I H, Langdon S P, Leach M O, Mann D J, Marshall J F, Martin L, Martin S G, Macdougall J E, Miles D W, Miller W R, Morris J R, Moss S M, Mullan P, Natrajan R, O’Connor J P, O’Connor R, Palmieri C, Pharoah P D, Rakha E A, Reed E, Robinson S P, Sahai E, Saxton J M, Schmid P, Smalley M J, Speirs V, Stein R, Stingl J, Streuli C H, Tutt A N, Velikova G, Walker R A, Watson C J, Williams K J, Young L S, Thompson A M. Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer. Breast Cancer Research, 2013, 15(5): R92CrossRefGoogle Scholar
  2. 2.
    Bonnal S, Vigevani L, Valcarcel J. The spliceosome as a target of novel antitumour drugs. Nature Reviews. Drug Discovery, 2012, 11 (11): 847–859CrossRefGoogle Scholar
  3. 3.
    Oltean S, Bates D O. Hallmarks of alternative splicing in cancer. Oncogene, 2014, 33(46): 5311–8CrossRefGoogle Scholar
  4. 4.
    Will C L, Luhrmann R. Spliceosome structure and function. Cold Spring Harbor Perspectives in Biology, 2011, 3(7): a003707CrossRefGoogle Scholar
  5. 5.
    Wang G S, Cooper T A. Splicing in disease: Disruption of the splicing code and the decoding machinery. Nature Reviews. Genetics, 2007, 8(10): 749–761CrossRefGoogle Scholar
  6. 6.
    Fu X D, Ares M Jr. Context-dependent control of alternative splicing by RNA-binding proteins. Nature Reviews. Genetics, 2014, 15(10): 689–701CrossRefGoogle Scholar
  7. 7.
    Jangi M, Sharp P A. Building robust transcriptomes with master splicing factors. Cell, 2014, 159(3): 487–498CrossRefGoogle Scholar
  8. 8.
    Kelemen O, Convertini P, Zhang Z, Wen Y, Shen M, Falaleeva M, Stamm S. Function of alternative splicing. Gene, 2013, 514(1): 1–30CrossRefGoogle Scholar
  9. 9.
    Venables J P. Aberrant and alternative splicing in cancer. Cancer Research, 2004, 64(21): 7647–7654CrossRefGoogle Scholar
  10. 10.
    Shkreta L, Bell B, Revil T, Venables J P, Prinos P, Elela S A, Chabot B. Cancer-Associated Perturbations in Alternative Pre-messenger RNA Splicing. Cancer Research and Treatment, 2013, 158: 41–94CrossRefGoogle Scholar
  11. 11.
    Watermann D O, Tang Y, Zur Hausen A, Jager M, Stamm S, Stickeler E. Splicing factor Tra2-β1 is specifically induced in breast cancer and regulates alternative splicing of the CD44 gene. Cancer Research, 2006, 66(9): 4774–4780CrossRefGoogle Scholar
  12. 12.
    Best A, Dagliesh C, Ehrmann I, Kheirollahi-Kouhestani M, Tyson- Capper A, Elliott D J. Expression of Tra2 β in Cancer Cells as a Potential Contributory Factor to Neoplasia and Metastasis. Int J Cell Biol, 2013, 2013: 843781CrossRefGoogle Scholar
  13. 13.
    Best A, Dalgliesh C, Kheirollahi-Kouhestani M, Danilenko M, Ehrmann I, Tyson-Capper A, Elliott D J. Tra2 protein biology and mechanisms of splicing control. Biochemical Society Transactions, 2014, 42(4): 1152–1158CrossRefGoogle Scholar
  14. 14.
    Clery A, Jayne S, Benderska N, Dominguez C, Stamm S, Allain F H. Molecular basis of purine-rich RNA recognition by the human SR-like protein Tra2-β1. Nature Structural & Molecular Biology, 2011, 18(4): 443–450CrossRefGoogle Scholar
  15. 15.
    Tsuda K, Someya T, Kuwasako K, Takahashi M, He F, Unzai S, Inoue M, Harada T, Watanabe S, Terada T, Kobayashi N, Shirouzu M, Kigawa T, Tanaka A, Sugano S, Guntert P, Yokoyama S, Muto Y. Structural basis for the dual RNA-recognition modes of human Tra2-β RRM. Nucleic Acids Research, 2011, 39(4): 1538–1553CrossRefGoogle Scholar
  16. 16.
    Eldridge A G, Li Y, Sharp P A, Blencowe B J. The SRm160/300 splicing coactivator is required for exon-enhancer function. Proceedings of the National Academy of Sciences of the United States of America, 1999, 96(11): 6125–6130CrossRefGoogle Scholar
  17. 17.
    Dettwiler S, Aringhieri C, Cardinale S, Keller W, Barabino S M. Distinct sequence motifs within the 68-kDa subunit of cleavage factor Im mediate RNA binding, protein-protein interactions, and subcellular localization. Journal of Biological Chemistry, 2004, 279(34): 35788–35797CrossRefGoogle Scholar
  18. 18.
    Venables J P, Elliott D J, Makarova O V, Makarov E M, Cooke H J, Eperon I C. RBMY, a probable human spermatogenesis factor, and other hnRNP G proteins interact with Tra2β and affect splicing. Human Molecular Genetics, 2000, 9(5): 685–694CrossRefGoogle Scholar
  19. 19.
    Hofmann Y, Lorson C L, Stamm S, Androphy E J, Wirth B. Htra2- β1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 (SMN2). Proceedings of the National Academy of Sciences of the United States of America, 2000, 97(17): 9618–9623CrossRefGoogle Scholar
  20. 20.
    Sakashita E, Tatsumi S, Werner D, Endo H, Mayeda A. Human RNPS1 and its associated factors: A versatile alternative pre-mRNA splicing regulator in vivo. Molecular and Cellular Biology, 2004, 24(3): 1174–1187CrossRefGoogle Scholar
  21. 21.
    Shin C, Feng Y, Manley J L. Dephosphorylated SRp38 acts as a splicing repressor in response to heat shock. Nature, 2004, 427(6974): 553–558CrossRefGoogle Scholar
  22. 22.
    Mende Y, Jakubik M, Riessland M, Schoenen F, Rossbach K, Kleinridders A, Kohler C, Buch T, Wirth B. Deficiency of the splicing factor Sfrs10 results in early embryonic lethality in mice and has no impact on full-length SMN/Smn splicing. Human Molecular Genetics, 2010, 19(11): 2154–2167CrossRefGoogle Scholar
  23. 23.
    Elliott D J, Best A, Dalgliesh C, Ehrmann I, Grellscheid S. How does Tra2β protein regulate tissue-specific RNA splicing? Biochemical Society Transactions, 2012, 40(4): 784–788CrossRefGoogle Scholar
  24. 24.
    Grellscheid S, Dalgliesh C, Storbeck M, Best A, Liu Y, Jakubik M, Mende Y, Ehrmann I, Curk T, Rossbach K, Bourgeois C F, Stevenin J, Grellscheid D, Jackson M S, Wirth B, Elliott D J. Identification of evolutionarily conserved exons as regulated targets for the splicing activator tra2β in development. PLoS Genetics, 2011, 7(12): e1002390CrossRefGoogle Scholar
  25. 25.
    Raponi M, Smith L D, Silipo M, Stuani C, Buratti E, Baralle D. BRCA1 exon 11 a model of long exon splicing regulation. RNA Biology, 2014, 11(4): 351–359CrossRefGoogle Scholar
  26. 26.
    Konig J, Zarnack K, Rot G, Curk T, Kayikci M, Zupan B, Turner D J, Luscombe N M, Ule J. iCLIP—transcriptome-wide mapping of protein-RNA interactions with individual nucleotide resolution. Journal of Visualized Experiments, 2011, 50: 2638Google Scholar
  27. 27.
    Best A, James K, Dalgliesh C, Hong E, Kheirolahi-Kouhestani M, Curk T, Xu Y, Danilenko M, Hussain R, Keavney B, Wipat A, Klinck R, Cowell I G, Cheong Lee K, Austin C A, Venables J P, Chabot B, Santibanez Koref M, Tyson-Capper A, Elliott D J. Human Tra2 proteins jointly control a CHEK1 splicing switch among alternative and constitutive target exons. Nature Communications, 2014, 5: 4760CrossRefGoogle Scholar
  28. 28.
    Dreszer T R, Karolchik D, Zweig A S, Hinrichs A S, Raney B J, Kuhn RM, Meyer L R, Wong M, Sloan C A, Rosenbloom K R, Roe G, Rhead B, Pohl A, Malladi V S, Li C H, Learned K, Kirkup V, Hsu F, Harte R A, Guruvadoo L, Goldman M, Giardine B M, Fujita P A, Diekhans M, Cline M S, Clawson H, Barber G P, Haussler D, James Kent W. The UCSC Genome Browser database: Extensions and updates 2011. Nucleic Acids Research, 2012, 40: 918–923CrossRefGoogle Scholar
  29. 29.
    Stoilov P, Daoud R, Nayler O, Stamm S. Human tra2-β1 autoregulates its protein concentration by influencing alternative splicing of its pre-mRNA. Human Molecular Genetics, 2004, 13(5): 509–524CrossRefGoogle Scholar
  30. 30.
    Hoglund A, Nilsson L M, Muralidharan S V, Hasvold L A, Merta P, Rudelius M, Nikolova V, Keller U, Nilsson J A. Therapeutic implications for the induced levels of Chk1 in Myc-expressing cancer cells. Clinical Cancer Research, 2011, 17(22): 7067–7079CrossRefGoogle Scholar
  31. 31.
    Lopez-Contreras A J, Gutierrez-Martinez P, Specks J, Rodrigo- Perez S, Fernandez-Capetillo O. An extra allele of Chk1 limits oncogene-induced replicative stress and promotes transformation. Journal of Experimental Medicine, 2012, 209(3): 455–461CrossRefGoogle Scholar
  32. 32.
    Hanahan D, Weinberg R A. Hallmarks of cancer: The next generation. Cell, 2011, 144(5): 646–674CrossRefGoogle Scholar
  33. 33.
    Hanahan D, Weinberg R A. The hallmarks of cancer. Cell, 2000, 100(1): 57–70CrossRefGoogle Scholar
  34. 34.
    Campaner S, Amati B. Two sides of the Myc-induced DNA damage response: From tumor suppression to tumor maintenance. Cell Division, 2012, 7(1): 6CrossRefGoogle Scholar
  35. 35.
    Murga M, Campaner S, Lopez-Contreras A J, Toledo L I, Soria R, Montana M F, D' Artista L, Schleker T, Guerra C, Garcia E, Barbacid M, Hidalgo M, Amati B, Fernandez-Capetillo O. Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors. Nature Structural & Molecular Biology, 2011, 18(12): 1331–1335CrossRefGoogle Scholar
  36. 36.
    Halazonetis T D, Gorgoulis V G, Bartek J. An oncogene-induced DNA damage model for cancer development. Science, 2008, 319 (5868): 1352–1355CrossRefGoogle Scholar
  37. 37.
    Bartek J, Mistrik M, Bartkova J. Thresholds of replication stress signaling in cancer development and treatment. Nature Structural & Molecular Biology, 2012, 19(1): 5–7CrossRefGoogle Scholar
  38. 38.
    McNeely S, Beckmann R, Bence Lin A K. CHEK again: Revisiting the development of CHK1 inhibitors for cancer therapy. Pharmacology & Therapeutics, 2014, 142(1): 1–10CrossRefGoogle Scholar
  39. 39.
    Chen T, Stephens P A, Middleton F K, Curtin N J. Targeting the S and G2 checkpoint to treat cancer. Drug Discovery Today, 2012, 17(5-6): 194–202CrossRefGoogle Scholar
  40. 40.
    Pabla N, Bhatt K, Dong Z. Checkpoint kinase 1 (Chk1)-short is a splice variant and endogenous inhibitor of Chk1 that regulates cell cycle and DNA damage checkpoints. Proceedings of the National Academy of Sciences of the United States of America, 2012, 109(1): 197–202CrossRefGoogle Scholar
  41. 41.
    Chen C R, Kang Y, Massague J. Defective repression of c-myc in breast cancer cells: A loss at the core of the transforming growth factor beta growth arrest program. Proceedings of the National Academy of Sciences of the United States of America, 2001, 98(3): 992–999CrossRefGoogle Scholar
  42. 42.
    Fogarty P, Kalpin R F, Sullivan W. The Drosophila maternal-effect mutation grapes causes a metaphase arrest at nuclear cycle 13. Development, 1994, 120(8): 2131–2142Google Scholar
  43. 43.
    Cao W M, Murao K, Imachi H, Yu X, Abe H, Yamauchi A, Niimi M, Miyauchi A, Wong N C, Ishida T. A mutant high-density lipoprotein receptor inhibits proliferation of human breast cancer cells. Cancer Research, 2004, 64(4): 1515–1521CrossRefGoogle Scholar
  44. 44.
    Woo H H, Yi X, Lamb T, Menzl I, Baker T, Shapiro D J, Chambers S K. Posttranscriptional suppression of proto-oncogene c-fms expression by vigilin in breast cancer. Molecular and Cellular Biology, 2011, 31(1): 215–225CrossRefGoogle Scholar
  45. 45.
    Cervigne N K, Machado J, Goswami R S, Sadikovic B, Bradley G, Perez-Ordonez B, Galloni N N, Gilbert R, Gullane P, Irish J C, Jurisica I, Reis P P, Kamel-Reid S. Recurrent genomic alterations in sequential progressive leukoplakia and oral cancer: Drivers of oral tumorigenesis? Human Molecular Genetics, 2014, 23(10): 2618–2628CrossRefGoogle Scholar
  46. 46.
    Parrish J K, Sechler M, Winn R A, Jedlicka P. The histone demethylase KDM3A is a microRNA-22-regulated tumor promoter in Ewing Sarcoma. Oncogene, 2013, 34(2): 257–262CrossRefGoogle Scholar
  47. 47.
    Hou J, Wu J, Dombkowski A, Zhang K, Holowatyj A, Boerner J L, Yang Z Q. Genomic amplification and a role in drug-resistance for the KDM5A histone demethylase in breast cancer. American Journal of Translational Research, 2012, 4(3): 247–256Google Scholar
  48. 48.
    Qin L, Wu Y L, Toneff M J, Li D, Liao L, Gao X, Bane F T, Tien J C, Xu Y, Feng Z, Yang Z, Theissen S M, Li Y, Young L, Xu J. NCOA1 Directly Targets M-CSF1 Expression to Promote Breast Cancer Metastasis. Cancer Research, 2014, 74(13): 3477–3488CrossRefGoogle Scholar
  49. 49.
    Huether R, Dong L, Chen X, Wu G, Parker M, Wei L, Ma J, Edmonson MN, Hedlund E K, Rusch MC, Shurtleff S A, Mulder H L, Boggs K, Vadordaria B, Cheng J, Yergeau D, Song G, Becksfort J, Lemmon G, Weber C, Cai Z, Dang J, Walsh M, Gedman A L, Faber Z, Easton J, Gruber T, Kriwacki R W, Partridge J F, Ding L, Wilson R K, Mardis E R, Mullighan C G, Gilbertson R J, Baker S J, Zambetti G, Ellison D W, Zhang J, Downing J R. The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes. Nature Communications, 2014, 5: 3630CrossRefGoogle Scholar
  50. 50.
    Bidkhori G, Narimani Z, Hosseini Ashtiani S, Moeini A, Nowzari- Dalini A, Masoudi-Nejad A. Reconstruction of an integrated genome-scale co-expression network reveals key modules involved in lung adenocarcinoma. PLoS One, 2013, 8(7): e67552CrossRefGoogle Scholar
  51. 51.
    Zhou B, Yuan T, Liu M, Liu H, Xie J, Shen Y, Chen P. Overexpression of the structural maintenance of chromosome 4 protein is associated with tumor de-differentiation, advanced stage and vascular invasion of primary liver cancer. Oncology Reports, 2012, 28(4): 1263–1268Google Scholar
  52. 52.
    Wu C H, Sahoo D, Arvanitis C, Bradon N, Dill D L, Felsher D W. Combined analysis of murine and human microarrays and ChIP analysis reveals genes associated with the ability of MYC to maintain tumorigenesis. PLoS Genetics, 2008, 4(6): e1000090CrossRefGoogle Scholar
  53. 53.
    Zhong J, Cao R X, Liu J H, Liu Y B, Wang J, Liu L P, Chen Y J, Yang J, Zhang Q H, Wu Y, Ding W J, Hong T, Xiao X H, Zu X Y, Wen G B. Nuclear loss of protein arginine N-methyltransferase 2 in breast carcinoma is associated with tumor grade and overexpression of cyclin D1 protein. Oncogene, 2013, 33(48): 5546–5558CrossRefGoogle Scholar
  54. 54.
    Piao L, Kang D, Suzuki T, Masuda A, Dohmae N, Nakamura Y, Hamamoto R. The Histone Methyltransferase SMYD2 Methylates PARP1 and Promotes Poly(ADP-ribosyl)ation Activity in Cancer Cells. Neoplasia, 2014, 16(3): 257–264CrossRefGoogle Scholar
  55. 55.
    Zhang X, Tanaka K, Yan J, Li J, Peng D, Jiang Y, Yang Z, Barton M C, Wen H, Shi X. Regulation of estrogen receptor alpha by histone methyltransferase SMYD2-mediated protein methylation. Proceedings of the National Academy of Sciences of the United States of America, 2013, 110(43): 17284–17289CrossRefGoogle Scholar
  56. 56.
    Sakamoto L H, Andrade R V, Felipe M S, Motoyama A B, Pittella Silva F. SMYD2 is highly expressed in pediatric acute lymphoblastic leukemia and constitutes a bad prognostic factor. Leukemia Research, 2014, 38(4): 496–502CrossRefGoogle Scholar
  57. 57.
    Huang A, Ho C S, Ponzielli R, Barsyte-Lovejoy D, Bouffet E, Picard D, Hawkins C E, Penn L Z. Identification of a novel c-Myc protein interactor, JPO2, with transforming activity in medulloblastoma cells. Cancer Research, 2005, 65(13): 5607–5619CrossRefGoogle Scholar
  58. 58.
    Singel S M, Cornelius C, Zaganjor E, Batten K, Sarode V R, Buckley D L, Peng Y, John G B, Li H C, Sadeghi N, Wright W E, Lum L, Corson T W, Shay J W. KIF14 Promotes AKT Phosphorylation and Contributes to Chemoresistance in Triple- Negative Breast Cancer. Neoplasia, 2014, 16(3): 247–256CrossRefGoogle Scholar
  59. 59.
    Singel SM, Cornelius C, Batten K, Fasciani G, Wright WE, Lum L, Shay J W. A targeted RNAi screen of the breast cancer genome identifies KIF14 and TLN1 as genes that modulate docetaxel chemosensitivity in triple-negative breast cancer. Clinical Cancer Research, 2013, 19(8): 2061–2070CrossRefGoogle Scholar
  60. 60.
    Mitra S, Mazumder Indra D, Basu P S, Mondal R K, Roy A, Roychoudhury S, Panda C K. Amplification of CyclinL1 in uterine cervical carcinoma has prognostic implications. Molecular Carcinogenesis, 2010, 49(11): 935–943CrossRefGoogle Scholar
  61. 61.
    Peng L, Yanjiao M, Ai-guo W, Pengtao G, Jianhua L, Ju Y, Hongsheng O, Xichen Z. A fine balance between CCNL1 and TIMP1 contributes to the development of breast cancer cells. Biochemical and Biophysical Research Communications, 2011, 409(2): 344–349CrossRefGoogle Scholar
  62. 62.
    Tanaka T, Nakatani T, Kamitani T. Inhibition of NEDD8- conjugation pathway by novel molecules: Potential approaches to anticancer therapy. Molecular Oncology, 2012, 6(3): 267–275CrossRefGoogle Scholar
  63. 63.
    PC O L. Penny S A, Dolan R T, Kelly C M, Madden S F, Rexhepaj E, Brennan D J, McCann A H, Ponten, F, Uhlen, M, Zagozdzon, R, Duffy, M J, Kell, M R, Jirstrom, K, Gallagher, W M. Systematic antibody generation and validation via tissue microarray technology leading to identification of a novel protein prognostic panel in breast cancer. BMC Cancer, 2013, 13: 175CrossRefGoogle Scholar
  64. 64.
    Mendes-Pereira A M, Sims D, Dexter T, Fenwick K, Assiotis I, Kozarewa I, Mitsopoulos C, Hakas J, Zvelebil M, Lord C J, Ashworth A. Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen. Proceedings of the National Academy of Sciences of the United States of America, 2012, 109(8): 2730–2735CrossRefGoogle Scholar
  65. 65.
    Rao M, Song W, Jiang A, Shyr Y, Lev S, Greenstein D, Brantley-Sieders D, Chen J. VAMP-associated protein B (VAPB) promotes breast tumor growth by modulation of Akt activity. PLoS One, 2012, 7(10): e46281CrossRefGoogle Scholar
  66. 66.
    Davis L M, Harris C, Tang L, Doherty P, Hraber P, Sakai Y, Bocklage T, Doeden K, Hall B, Alsobrook J, Rabinowitz I, Williams T M, Hozier J. Amplification patterns of three genomic regions predict distant recurrence in breast carcinoma. Journal of Molecular Diagnostics, 2007, 9(3): 327–336CrossRefGoogle Scholar
  67. 67.
    Lei Y, Henderson B R, Emmanuel C, Harnett P R, Defazio A. Inhibition of ANKRD1 sensitizes human ovarian cancer cells to endoplasmic reticulum stress-induced apoptosis. Oncogene, 2014, 34(4): 485–495CrossRefGoogle Scholar
  68. 68.
    Trendel J A, Ellis N, Sarver J G, Klis W A, Dhananjeyan M, Bykowski C A, Reese M D, Erhardt P W. Catalytically active peptidylglycine alpha-amidating monooxygenase in the media of androgen-independent prostate cancer cell lines. Journal of Biomolecular Screening, 2008, 13(8): 804–809CrossRefGoogle Scholar
  69. 69.
    Lee G, Blenis J. Akt-ivation of RNA splicing. Molecular Cell, 2014, 53(4): 519–520CrossRefGoogle Scholar
  70. 70.
    Fu X, Meng Z, Liang W, Tian Y, Wang X, Han W, Lou G, Lou F, Yen Y, Yu H, Jove R, Huang W. miR-26a enhances miRNA biogenesis by targeting Lin28B and Zcchc11 to suppress tumor growth and metastasis. Oncogene, 2013, 33(34): 4296–4306CrossRefGoogle Scholar
  71. 71.
    Piskounova E, Polytarchou C, Thornton J E, La Pierre R J, Pothoulakis C, Hagan J P, Iliopoulos D, Gregory R I. Lin28A and Lin28B inhibit let-7 microRNA biogenesis by distinct mechanisms. Cell, 2011, 147(5): 1066–1079CrossRefGoogle Scholar
  72. 72.
    Schmidt M J, West S, Norbury C J. The human cytoplasmic RNA terminal U-transferase ZCCHC11 targets histone mRNAs for degradation. RNA, 2011, 17(1): 39–44CrossRefGoogle Scholar
  73. 73.
    Albiges L, Goubar A, Scott V, Vicier C, Lefebvre C, Alsafadi S, Commo F, Saghatchian M, Lazar V, Dessen P, Delaloge S, Andre F, Quidville V. Chk1 as a new therapeutic target in triple-negative breast cancer. Breast, 2014, 23(3): 250–258CrossRefGoogle Scholar
  74. 74.
    Ma C X, Cai S, Li S, Ryan C E, Guo Z, Schaiff WT, Lin L, Hoog J, Goiffon R J, Prat A, Aft R L, Ellis MJ, Piwnica-Worms H. Targeting Chk1 in p53-deficient triple-negative breast cancer is therapeutically beneficial in human-in-mouse tumor models. Journal of Clinical Investigation, 2012, 122(4): 1541–1552CrossRefGoogle Scholar
  75. 75.
    Zhang Y, Hunter T. Roles of Chk1 in cell biology and cancer therapy. International Journal of Cancer, 2014, 134(5): 1013–1023CrossRefGoogle Scholar
  76. 76.
    Anderson E S, Lin C H, Xiao X, Stoilov P, Burge C B, Black D L. The cardiotonic steroid digitoxin regulates alternative splicing through depletion of the splicing factors SRSF3 and TRA2B. RNA, 2012, 18(5): 1041–1049CrossRefGoogle Scholar
  77. 77.
    Novoyatleva T, Heinrich B, Tang Y, Benderska N, Butchbach M E, Lorson C L, Lorson M A, Ben-Dov C, Fehlbaum P, Bracco L, Burghes A H, Bollen M, Stamm S. Protein phosphatase 1 binds to the RNA recognition motif of several splicing factors and regulates alternative pre-mRNA processing. Human Molecular Genetics, 2008, 17(1): 52–70CrossRefGoogle Scholar
  78. 78.
    Katzenberger R J, Marengo M S, Wassarman D A. Control of alternative splicing by signal-dependent degradation of splicingregulatory proteins. Journal of Biological Chemistry, 2009, 284(16): 10737–10746CrossRefGoogle Scholar
  79. 79.
    Bechara E G, Sebestyen E, Bernardis I, Eyras E, Valcarcel J. RBM5, 6, and 10 differentially regulate NUMB alternative splicing to control cancer cell proliferation. Molecular Cell, 2013, 52(5): 720–733CrossRefGoogle Scholar
  80. 80.
    Nam E A, Cortez D. ATR signalling: more than meeting at the fork. Biochemical Journal, 2011, 436(3): 527–536CrossRefGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Andrew Best
    • 1
  • Katherine James
    • 2
  • Gerald Hysenaj
    • 1
  • Alison Tyson-Capper
    • 3
  • David J. Elliott
    • 1
  1. 1.Institute of Genetic MedicineNewcastle UniversityNewcastleUK
  2. 2.Interdisciplinary Computing and Complex BioSystems Research Group and Centre for Bacterial Cell BiologyNewcastle UniversityNewcastleUK
  3. 3.Institute for Cellular MedicineNewcastle UniversityNewcastleUK

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