Positions for prospective BSc./MSc./PhD. students and postdocs are available. (We are always looking for talented and motivated BSc./MSc./PhD. students and postdocs. I encourage you to contact me at dalibor.blazek at ceitec.muni.cz in case you are interested in our ongoing projects or research topics in broader terms.)
PhD topics:
Doctoral study program: Life Sciences / Biomedical Sciences (Molecular Medicine)
Research area:
RNA/nucleic acids research in health, cancer biology.
Topic titles:
- Characterization of cyclin-dependent kinase 12 (CDK12) substrates and their roles in regulation of transcription and tumorigenesis
- Functions of cyclin-dependent kinase 11 (CDK11) in regulation of gene expression and tumorigenesis
1. Characterization of cyclin-dependent kinase 12 (CDK12) substrates and their roles in regulation of transcription and tumorigenesis
Supervisor: Dalibor Blažek, Ph.D.
Annotation:
CDK12 is transcriptional cyclin-dependent kinase (CDK) found mutated in various cancers. In previous studies we found that CDK12 maintains genome stability via optimal transcription of key homologous recombination repair pathway genes including BRCA1 and plays a role in cell cycle progression by regulating processivity of RNA Polymerase II at core DNA replication genes. Apart from the C-terminal domain of RNA Polymerase II other cellular substrates of CDK12 are not known. In this research we propose using a screen in cells carrying an analog sensitive mutant of CDK12 to discover its novel cellular substrates. The substrates and their roles in normal and cancerous cells will be characterized by advanced techniques of molecular biology and biochemistry.
Recommended literature:
- Pilarova K, Herudek J, Blazek D.*: CDK12: Cellular functions and therapeutic potential of versatile player in cancer: Nucleic Acids Research Cancer (Oxford University Press) k2 (1): zcaa003 (2020)
- Chirackal Manavalan A.P., Pilarova K., Kluge M., Bartholomeeusen K., Oppelt J., Khirsariya P., Paruch K., Krejci L., Friedel C.C., Blazek D* : CDK12 controls G1/S progression via regulating RNAPII processivity at core DNA replication genes. EMBO reports 20(9):47592 (2019)
- Ekumi KM, Paculova H, Lenasi T, Pospichalova V, Bösken CA, Rybarikova J, Bryja V, Geyer M, Blazek D*, Barboric M*. Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex. Nucleic Acids Research 43(5):2575-89 (2015)
- Bösken CA, Farnung L, Hintermair C, Merzel Schachter M, Vogel-Bachmayr K, Blazek D, Anand K, Fisher RP, Eick D, Geyer M. The structure and substrate specificity of human Cdk12/Cyclin K. Nature Communications 5 (2014).
- Blazek D*., Kohoutek J., Bartholomeeusen K., Johansen E., Hulinkova P., Luo Z., Cimermancic P.,Ule J., Peterlin B.M.: The CycK/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes. Genes and Development 25 (20): 2158-2172 (2011).
Requirements on candidates:
Background in molecular biology, biochemistry or life sciences. Interest in bioinformatics and data analyses is desirable.
Keywords: CDK12, transcription, mRNA processing, RNA polymerase II, cancer, genomics, proteomics, substrates, kinase inhibitors
2. Functions of cyclin-dependent kinase 11 (CDK11) in regulation of gene expression and tumorigenesis
Supervisor: Dalibor Blažek, Ph.D.
Annotation:
Cyclin-dependent kinase 11 (CDK11) is ubiquitously expressed in all tissues indicating an important role for CDK11 in cells. Our recent studies has shown CDK11 plays key roles in transcription of replication-dependent histone genes and in co-transcriptional mRNA splicing (1, 2). Notably, several recent studies identified CDK11 as a candidate essential gene for growth of several cancers therefore, understanding the molecular mechanism(s) of CDK11-dependent gene expression is also of significant clinical interest. In this research we will use CDK11 inhibitors and advanced techniques of molecular biology and biochemistry to characterize roles of CDK11 in regulation of gene expression and tumorigenesis.
Recommended literature:
- Hluchy M, Gajduskova, P., Ruiz de los Mozos I., Rajecky M., Kluge M., Berger BT., Slaba Z. Potesil D., Weis E., Ule J., Zdrahal Z., Knapp S., Paruch K., Friedel CC., Blazek D*. CDK11 regulates pre-mRNA splicing by phosphorylation of SF3B1. Nature; 609(7928):829-834 (2022)
- Gajduskova, P., Ruiz de Los Mozos I, Rajecky M., Hluchy M., Ule J., Blazek D*: CDK11 is required for transcription of replication dependent histone genes. Nature Structural & Molecular Biology 27 (5):500-510 (2020)
Requirements on candidates:
Background in molecular biology, biochemistry or life sciences. Interest in bioinformatics and data analyses is desirable.
Keywords:
CDK11, mRNA splicing, replication-dependent histone genes, SF3B1, cancer, genomics, proteomics, kinase inhibitors, OTS964