Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex

Nucleic Acids Research

Volumn 43, Issue 5, 2015, Pages 2575-2589

  Ekumi, Kingsley M ^a   Paculova, Hana ^b   Lenasi, Tina ^a   Pospichalova, Vendula ^b   Bösken, Christian A ^c   Rybarikova, Jana ^b   Bryja, Vitezslav ^b,d   Geyer, Matthias ^c   Blazek, Dalibor ^b   Barboric, Matjaz ^a  

^a UNIVERSITY OF HELSINKI   (Finland)

^b MASARYK UNIVERSITY   (Czech Republic)

^c CENTER OF ADVANCED EUROPEAN STUDIES AND RESEARCH CAESAR   (Germany)

^d INSTITUTE OF BIOPHYSICS   (Czech Republic)

Author keywords

[No Author keywords available]

Indexed keywords

CYCK PROTEIN; CYCLIN DEPENDENT KINASE; CYCLIN DEPENDENT KINASE 12; RNA POLYMERASE II; SERINE; UNCLASSIFIED DRUG; CCNK PROTEIN, HUMAN; CDK12 PROTEIN, HUMAN; CYCLINE; MULTIPROTEIN COMPLEX; PROTEIN BINDING;

ARTICLE; CARCINOGENESIS; CDK12 GENE; CLINICAL ARTICLE; CONTROLLED STUDY; CORRELATIONAL STUDY; DNA REPAIR; DNA TRANSCRIPTION; DOUBLE STRANDED DNA BREAK; DOWN REGULATION; ENZYME ACTIVATION; ENZYME ACTIVITY; ENZYME INACTIVATION; ENZYME PHOSPHORYLATION; FEMALE; GENE; GENE DELETION; GENE EXPRESSION REGULATION; GENE INSERTION; GENOMIC INSTABILITY; HEK293 CELL LINE; HOMOLOGOUS RECOMBINATION; HUMAN; LOSS OF FUNCTION MUTATION; MISSENSE MUTATION; MOLECULAR DYNAMICS; NONSENSE MUTATION; OVARY CARCINOMA; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN FORMATION; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; AMINO ACID SEQUENCE; CHEMICAL STRUCTURE; CHEMISTRY; GENETICS; HELA CELL LINE; METABOLISM; MOLECULAR GENETICS; MUTATION; OVARY TUMOR; PATHOLOGY; PROTEIN TERTIARY STRUCTURE; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; RNA INTERFERENCE; SEQUENCE HOMOLOGY; TUMOR CELL LINE; WESTERN BLOTTING;

AMINO ACID SEQUENCE; BLOTTING, WESTERN; CELL LINE, TUMOR; CYCLIN-DEPENDENT KINASES; CYCLINS; DNA REPAIR; FEMALE; GENE EXPRESSION REGULATION, NEOPLASTIC; HEK293 CELLS; HELA CELLS; HUMANS; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; MULTIPROTEIN COMPLEXES; MUTATION; OVARIAN NEOPLASMS; PROTEIN BINDING; PROTEIN STRUCTURE, TERTIARY; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; RNA INTERFERENCE; SEQUENCE HOMOLOGY, AMINO ACID;

EID: 84937622540     PISSN: 03051048     EISSN: 13624962     Source Type: Journal    
DOI: 10.1093/nar/gkv101     Document Type: Article

References (55)

1. Fuda, N. J., Ardehali, M. B. and Lis, J. T. (2009) Defining mechanisms that regulate RNA polymerase II transcription in vivo. Nature, 461, 186-192.
2. Eick, D. and Geyer, M. (2013) The RNA polymerase II carboxy-terminal domain (CTD) code. Chem. Rev., 113, 8456-8490.
3. Zhou, Q., Li, T. and Price, D. H. (2012) RNA polymerase II elongation control. Annu. Rev. Biochem., 81, 119-143.
4. Lenasi, T. and Barboric, M. (2010) P-TEFb stimulates transcription elongation and pre-mRNA splicing through multilateral mechanisms. RNA Biol, 7, 145-150.
5. Bartkowiak, B., Liu, P., Phatnani, H. P., Fuda, NJ., Cooper, J. J., Price, D. H., Adelman, K., Lis, J. T. and Greenleaf, A. L. (2010) CDK12 is a transcription elongation-associated CTD kinase, the metazoan ortholog of yeast Ctk1. Genes Dev, 24, 2303-2316.
6. Blazek, D, Kohoutek, J., Bartholomeeusen, K., Johansen, E., Hulinkova, P, Luo, Z., Cimermancic, P, Ule, J. and Peterlin, B. M. (2011) The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes. Genes Dev., 25, 2158-2172.
7. Cheng, S. W., Kuzyk, M. A., Moradian, A., Ichu, TA., Chang, VC, Tien, J. F., Vollett, S. E., Griffith, M., Marra, M. A. and Morin, G. B. (2012) Interaction of cyclin-dependent kinase 12/CrkRS with cyclin K1 is required for the phosphorylation of the C-terminal domain of RNA polymerase II. Mol Cell. Biol, 32, 4691-4704.
8. Davidson, L., Muniz, L. and West, S. (2014) 3' end formation of pre-mRNA and phosphorylation of Ser2 on the RNA polymerase II CTD are reciprocally coupled in human cells. Genes Dev., 28, 342-356.
9. Bosken, CA., Farnung, L., Hintermair, C, Merzel Schachter, M., Vogel-Bachmayr, K., Blazek, D, Anand, K., Fisher, R. P, Eick, D. and Geyer, M. (2014) The structure and substrate specificity of human Cdk12/Cyclin K. Nat. Commun., 5, 3505.
10. Cho, E. J., Kobor, M. S., Kim, M., Greenblatt, J. and Buratowski, S. (2001) Opposing effects of Ctk1 kinase and Fcp1 phosphatase at Ser 2 of the RNA polymerase II C-terminal domain. Genes Dev., 15, 3319-3329.
11. Coudreuse, D., van Bakel, H., Dewez, M., Soutourina, J., Parnell, T, Vandenhaute, J., Cairns, B., Werner, M. and Hermand, D. (2010) A gene-specific requirement of RNA polymerase II CTD phosphorylation for sexual differentiation in S. pombe. Curr. Biol., 20, 1053-1064.
12. Dai, Q., Lei, T., Zhao, C., Zhong, J., Tang, Y. Z., Chen, B., Yang, J., Li, C., Wang, S., Song, X. et al. (2012) Cyclin K-containing kinase complexes maintain self-renewal in murine embryonic stem cells. J. Biol. Chem., 287, 25344-25352.
13. Rahl, P. B., Lin, C. Y., Seila, A. C., Flynn, R. A., McCuine, S., Burge, C. B., Sharp, P. A. and Young, R. A. (2010) c-Myc regulates transcriptional pause release. Cell, 141, 432-445.
14. Chao, S. H. and Price, D. H. (2001) Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo. J. Biol. Chem., 276, 31793-31799.
15. Ostapenko, D. and Solomon, M. J. (2003) Budding yeast CTDK-I is required for DNA damage-induced transcription. Eukaryot. Cell, 2, 274-283.
16. Winsor, T. S., Bartkowiak, B., Bennett, C. B. and Greenleaf, A. L. (2013) A DNA damage response system associated with the phosphoCTD of elongating RNA polymerase II. PLoS One, 8, e60909.
17. Lee, T. I. and Young, R. A. (2013) Transcriptional regulation and its misregulation in disease. Cell, 152, 1237-1251.
18. Smith, E., Lin, C. and Shilatifard, A. (2011) The super elongation complex (SEC) and MLL in development and disease. Genes Dev., 25, 661-672.
19. Ji, X., Lu, H., Zhou, Q. and Luo, K. (2014) LARP7 suppresses P-TEFb activity to inhibit breast cancer progression and metastasis. Elife, 3, e02907.
20. Benusiglio, P. R., Pharoah, P. D., Smith, P. L., Lesueur, F., Conroy, D., Luben, R. N., Dew, G., Jordan, C., Dunning, A., Easton, D. F. et al. (2006) HapMap-based study of the 17q21 ERBB2 amplicon in susceptibility to breast cancer. B r. J. Cancer, 95, 1689-1695.
21. Sircoulomb, F., Bekhouche, I., Finetti, P., Adelaide, J., Hamida, A., Bonansea, J., Raynaud, S., Innocenti, C., Charafe-Jauffret, E., Tarpin, C. et al. (2010) Genome profiling of ERBB2-amplified breast cancers. BMC Cancer, 10, 539.
22. Natrajan, R., Wilkerson, P. M., Marchio, C., Piscuoglio, S., Ng, C. K., Wai, P., Lambros, M. B., Samartzis, E. P., Dedes, K. J., Frankum, J. et al. (2014) Characterization of the genomic features and expressed fusion genes in micropapillary carcinomas of the breast. J. Pathol., 232, 553-565.
23. Zang, Z. J., Ong, C. K., Cutcutache, I., Yu, W., Zhang, S. L., Huang, D., Ler, L. D., Dykema, K., Gan, A., Tao, J. et al. (2011) Genetic and structural variation in the gastric cancer kinome revealed through targeted deep sequencing. Cancer Res., 71, 29-39.
24. Cancer Genome Atlas Research Network. (2011) Integrated genomic analyses of ovarian carcinoma. Nature, 474, 609-615.
25. Carter, S. L., Cibulskis, K., Helman, E., McKenna, A., Shen, H., Zack, T., Laird, P. W., Onofrio, R. C., Winckler, W., Weir, B. A. et al. (2012) Absolute quantification of somatic DNA alterations in human cancer. Nat. Biotechnol., 30, 413-421.
26. Jasin, M. and Rothstein, R. (2013) Repair of strand breaks by homologous recombination. Cold Spring Harb. Perspect. Biol., 5, a012740.
27. Blazek, D. (2012) The cyclin K/Cdk12 complex: an emerging new player in the maintenance of genome stability. Cell Cycle, 11, 1049-1050.
28. Lenasi, T., Peterlin, B. M. and Barboric, M. (2011) Cap-binding protein complex links pre-mRNA capping to transcription elongation and alternative splicing through positive transcription elongation factor b (P-TEFb). J. Biol. Chem., 286, 22758-22768.
29. Pavletich, N. P. (1999) Mechanisms of cyclin-dependent kinase regulation: structures of Cdks, their cyclin activators, and Cip and INK4 inhibitors. J. Mol. Biol., 287, 821-828.
30. Larochelle, S., Amat, R., Glover-Cutter, K., Sanso, M., Zhang, C., Allen, J. J., Shokat, K. M., Bentley, D. L. and Fisher, R. P. (2012) Cyclin-dependent kinase control of the initiation-to-elongation switch of RNA polymerase II. Nat. Struct. Mol. Biol., 19, 1108-1115.
31. Ding, L., Getz, G., Wheeler, D. A., Mardis, E. R., McLellan, M. D., Cibulskis, K., Sougnez, C., Greulich, H., Muzny, D. M., Morgan, M. B. et al. (2008) Somatic mutations affect key pathways in lung adenocarcinoma. Nature, 455, 1069-1075.
32. Kan, Z., Jaiswal, B. S., Stinson, J., Janakiraman, V., Bhatt, D., Stern, H. M., Yue, P., Haverty, P. M., Bourgon, R., Zheng, J. et al. (2010) Diverse somatic mutation patterns and pathway alterations in human cancers. Nature, 466, 869-873.
33. Drogat, J. and Hermand, D. (2012) Gene-specific requirement of RNA polymerase II CTD phosphorylation. Mol. Microbiol., 84, 995-1004.
34. Kohoutek, J. and Blazek, D. (2012) Cyclin K goes with Cdk12 and Cdk13. Cell Div., 7, 12.
35. Tiley, L. S., Madore, S. J., Malim, M. H. and Cullen, B. R. (1992) The VP16 transcription activation domain is functional when targeted to a promoter-proximal RNA sequence. Genes Dev., 6, 2077-2087.
36. Garriga, J., Mayol, X. and Grana, X. (1996) The CDC2-related kinase PITALRE is the catalytic subunit of active multimeric protein complexes. Biochem. J., 319, 293-298.
37. San Filippo, J., Sung, P. and Klein, H. (2008) Mechanism of eukaryotic homologous recombination. Annu. Rev. Biochem., 77, 229-257.
38. Pierce, A. J., Johnson, R. D., Thompson, L. H. and Jasin, M. (1999) XRCC3 promotes homology-directed repair of DNA damage in mammalian cells. Genes Dev., 13, 2633-2638.
39. Bajrami, I., Frankum, J. R., Konde, A., Miller, R. E., Rehman, F. L., Brough, R., Campbell, J., Sims, D., Rafq, R., Hooper, S. et al. (2014) Genome-wide profiling of genetic synthetic lethality identifies CDK12 as a novel determinant of PARP1/2 inhibitor sensitivity. Cancer Res., 74, 287-297.
40. Joshi, P. M., Sutor, S. L., Huntoon, C. J. and Karnitz, L. M. (2014) Ovarian cancer-associated mutations disable catalytic activity of CDK12, a kinase that promotes homologous recombination repair and resistance to cisplatin and poly (ADP-ribose) polymerase inhibitors. J. Biol. Chem., 289, 9247-9253.
41. Malumbres, M. and Barbacid, M. (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat. Rev. Cancer, 9, 153-166.
42. Firestein, R., Bass, A. J., Kim, S. Y., Dunn, I. F., Silver, S. J., Guney, I., Freed, E., Ligon, A. H., Vena, N., Ogino, S. et al. (2008) CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity. Nature, 455, 547-551.
43. Chen, H. H., Wang, Y. C. and Fann, M. J. (2006) Identification and characterization of the CDK12/cyclin L1 complex involved in alternative splicing regulation. Mol. Cell. Biol., 26, 2736-2745.
44. Eifer, T. T., Shao, W., Bartholomeeusen, K., Fujinaga, K., Jager, S., Johnson, J. R., Luo, Z., Krogan, N. J. and Peterlin, B. M. (2015) Cyclin-dependent kinase 12 increases 3' end processing of growth factor-induced c-FOS transcripts. Mol. Cell. Biol, 35, 468-478.
45. Bartkowiak, B. and Greenleaf, A. L. (2014) Expression, purification, and identification of associated proteins of the full length hCDK12/CyclinK complex. J. Biol. Chem., 290, 1786-1795.
46. Morrison, C, Sonoda, E., Takao, N., Shinohara, A., Yamamoto, K. and Takeda, S. (2000) The controlling role of ATM in homologous recombinational repair of DNA damage. EMBO J., 19, 463-471.
47. Moynahan, M. E., Chiu, J. W., Koller, B. H. and Jasin, M. (1999) Brca1 controls homology-directed DNA repair. Mol. Cell, 4, 511-518.
48. Nakanishi, K., Yang, YG., Pierce, A. J., Taniguchi, T, Digweed, M., D'Andrea, A. D., Wang, Z. Q. and Jasin, M. (2005) Human Fanconi anemia monoubiquitination pathway promotes homologous DNA repair. Proc. Natl. Acad. Sci. U. S. A., 102, 1110-1115.
49. McCabe, N, Turner, NC, Lord, C. J., Kluzek, K., Bialkowska, A., Swift, S., Giavara, S., O'Connor, M. J., Tutt, A. N, Zdzienicka, M. Z. et al. (2006) Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly (ADP-ribose) polymerase inhibition. Cancer Res., 66, 8109-8115.
50. Marechal, A. and Zou, L. (2013) DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb. Perspect. Biol, 5, a012716.
51. Smogorzewska, A., Matsuoka, S., Vinciguerra, P., McDonald, E. R. 3rd, Hurov, K. E., Luo, J., Ballif, B. A., Gygi, S. P., Hofmann, K., D'Andrea, A. D et al. (2007) Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell, 129, 289-301.
52. Moynahan, M. E. and Jasin, M. (2010) Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat. Rev. Mol. Cell Biol, 11, 196-207.
53. Hanahan, D. and Weinberg, R. A. (2011) Hallmarks of cancer: the next generation. Cell, 144, 646-674.
54. Sirbu, B. M. and Cortez, D (2013) DNA damage response: three levels of DNA repair regulation. Cold Spring Harb. Perspect. Biol., 5, a012724.
55. O'Connell, B. C, Adamson, B., Lydeard, J. R., Sowa, M. E., Ciccia, A., Bredemeyer, A. L., Schlabach, M., Gygi, S. P., Elledge, S. J. and Harper, J. W. (2010) A genome-wide camptothecin sensitivity screen identifies a mammalian MMS22L-NFKBIL2 complex required for genomic stability. Mol. Cell, 40, 645-657.