CEITEC scientists identify a missing link in the development of cancer


Billions of cells in the human body divide each day.


This intricate division (aka cell cycle) includes four highly regulated phases (G1 ->S ->G2 ->M).



 Cell cycle (Source: https://teachmephysiology.com/)


A slight irregularity is enough to result in uncontrolled division, the hallmark of cancer – when the cell cycle goes haywire.


A normal cell-cycle progression requires a dedicated biological machinery, working hand-in-hand to carry out this sophisticated process. Cyclin-Dependent Kinases (CDK) are a specific set of proteins that regulates the pace of the cell cycle phases and dictates the cell to move from one stage to another.


Lower organisms have fewer CDKs, but higher and more complex creatures like humans possess 20 types of CDKs.


In this study (1), the research group of Dr. Dalibor Blažek at CEITEC displayed the function of CDK12 in humans.


Dr. Dalibor Blažek  (Photography by Emil Gallík)



CDK12 emerged as an anti-cancer target


Dr. Blažek explains, “CDK12 was not extensively studied. We discovered (2) in 2011 that this kinase regulates the expression of DNA damage response (A network of cellular surveillance pathways that sense, signal, and repair DNA wounds) genes." 


"In the last six years, CDK12 has surfaced as a major anti-cancer target.”


“When CDK12 is aberrant in a cell, DNA damage and genome instability occur, but the mechanistic reasons behind those effects were not clear.”


“Previous studies lacked an inhibitor tool to aid in the understanding of CDK12 function. In this study, we have successfully prepared a cell line where CDK12 can be quickly and specifically inhibited, which unraveled the mechanism,” Dr. Blažek added.



Inhibition of CDK12 disrupts the cell cycle


Dr. Blažek states, “When we inhibited CDK12, in addition to the DNA damage response genes, the cell cycle genes - especially which regulate the G1-> S progression (S Phase: During the synthesis or S phase, DNA replication is taking place and the amount of DNA within the cell doubles) were also affected.”


“Moreover, astonishingly, we found a precise connection between CDK12 and transcription (the process of copying genetic information from a DNA to an RNA).”


Appropriate transcriptional regulation is needed for the G1-> S progression. The expression of various DNA replication genes is essential for this cell cycle junction. The RNA Polymerase II (RNAPII) enzyme transcribes these genes.



Dr. Anil Manavalan (the lead author of the study) and Dr. Dalibor Blažek (Photography by Emil Gallík)



Dr. Blažek affirms, “Once we inhibited the CDK12, the RNAPII falls off many DNA replication genes, and their transcription remains incomplete. As a result, shorter non-functional transcripts (mRNA) are formed. Failure in the expression of DNA replication and DNA damage response genes leads to genome instability in the cells, underpinning cancer.”



How will the research help us in the long run?


Dr. Blažek pledges, “In 7% of prostate cancers, inactivation of CDK12 was reported. Importantly, these aberrations are linked with a very unique genome instability phenotype. Additionally, CDK12 is impaired in 20-30% of breast cancers and ovarian cancers. Thus, we can utilize CDK12 as a biomarker for these types of cancers, which can help the physicians streamline further patient-specific anti-cancer therapy.”


“There is a high interest to find specific inhibitors of this kinase. Our research of CDK12-dependent mechanisms in cells, apart from very interesting biology, will open the door to the application of these inhibitors in specific anti-cancer treatments.”


Dr. Blažek confirms, “The vision of our lab is to find out what these kinases are doing in our cells, and apply our knowledge to aid cancer research.”


“In this particular study, we had a wonderful collaboration with research groups of Caroline Friedel, the bioinformatician from LMU, Munich, Germany and with Lumir Krejci, the biochemist, and Kamil Paruch, the medicinal chemist from Masaryk University,” conveys Dr. Blažek, proving again – Science is a team-game!



References

  1. CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes. Chirackal Manavalan AP, Pilarova K, Kluge M, Bartholomeeusen K, Rajecky M, Oppelt J, Khirsariya P, Paruch K, Krejci L, Friedel CC, Blazek D. EMBO Rep. 2019 Jul 25:e47592. doi: 10.15252/embr.201847592
  2. The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes. Blažek D *, Kohoutek J, Bartholomeeusen K, Johansen E, Hulinkova P, Luo Z, Cimermancic P, Ule J, Peterlin BM. Genes and Development. 2011 Oct 15;25(20):2158-72. doi: 10.1101/gad.16962311.



Written by Somsuvro Basu