Related Experiment Video

Updated: Jan 26, 2026

Author Spotlight: Deciphering the Role of ATM in Ataxia-Telangiectasia and the Associated Cerebellar Degeneration
08:41

Author Spotlight: Deciphering the Role of ATM in Ataxia-Telangiectasia and the Associated Cerebellar Degeneration

Published on: December 27, 2024

2.0K

CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation

Malgorzata Krajewska1,2, Ruben Dries1,2,3, Andrew V Grassetti4

  • 1Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA, 02115, USA.

Nature Communications
|April 17, 2019
PubMed

Insights

Cyclin-dependent kinase 12 (CDK12) inhibition affects long DNA damage response (DDR) genes by causing premature transcription termination. This occurs due to increased intronic polyadenylation sites, impacting gene expression.

Area of Science:

  • Molecular Biology
  • Cancer Genomics

Background:

  • Cyclin-dependent kinase 12 (CDK12) regulates transcription elongation via RNA polymerase II phosphorylation.
  • CDK12 influences DNA damage response (DDR) and mRNA processing genes, but its selectivity mechanisms are unclear.

Purpose of the Study:

  • To elucidate the mechanisms behind CDK12's selective regulation of gene expression, particularly in cancer cells.
  • To investigate the impact of CDK12 inhibition on gene length and the DNA damage response.

Main Methods:

  • Utilized CDK12 inhibition in cancer cells lacking CDK12 mutations.
  • Analyzed gene length-dependent elongation defects and premature cleavage and polyadenylation (PCPA).
  • Performed phosphoproteomic analysis of pre-mRNA processing factors.

Main Results:

  • CDK12 inhibition caused gene length-dependent elongation defects, specifically affecting long (>45 kb) genes.
  • A significant proportion of affected long genes were involved in the DDR.
  • Increased intronic polyadenylation sites were observed, particularly in DDR genes, correlating with early termination.

Conclusions:

  • CDK12 inhibition leads to premature termination of long genes, especially DDR genes, through increased intronic polyadenylation.
  • DDR genes are uniquely vulnerable to CDK12 inhibition due to their length and specific RNA processing factor ratios.
  • CDK12 directly phosphorylates pre-mRNA processing factors, linking its kinase activity to PCPA regulation.

More Related Videos

Two- and Three-Dimensional Live Cell Imaging of DNA Damage Response Proteins10:24

Two- and Three-Dimensional Live Cell Imaging of DNA Damage Response Proteins

Published on: September 28, 2012

14.6K
Immunofluorescence Imaging of DNA Damage and Repair Foci in Human Colon Cancer Cells05:18

Immunofluorescence Imaging of DNA Damage and Repair Foci in Human Colon Cancer Cells

Published on: June 9, 2020

11.8K

Related Concept Videos

DNA Damage Can Stall the Cell Cycle02:36

DNA Damage Can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
3.1K
DNA Damage can Stall the Cell Cycle02:36

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
10.0K
Overview of DNA Repair02:25

Overview of DNA Repair

In order to be passed through generations, genomic DNA must be undamaged and error-free. However, every day, DNA in a cell undergoes several thousand to a million damaging events by natural causes and external factors. Ionizing radiation such as UV rays, free radicals produced during cellular respiration, and hydrolytic damage from metabolic reactions can alter the structure of DNA. Damages caused include single-base alteration, base dimerization, chain breaks, and cross-linkage.
Chemically...
33.5K
Cleavage and Blastulation01:33

Cleavage and Blastulation

After a large-single-celled zygote is produced via fertilization, the process of cleavage occurs while zygotes travel through the uterine tube. Cleavage is a mitotic cell division that does not result in growth. With each round of successive cell division, daughter cells get increasingly smaller.
50.0K
Loss of Tumor Suppressor Gene Functions01:12

Loss of Tumor Suppressor Gene Functions

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
5.9K
Gene Conversion02:08

Gene Conversion

Other than maintaining genome stability via DNA repair, homologous recombination plays an important role in diversifying the genome. In fact, the recombination of sequences forms the molecular basis of genomic evolution. Random and non-random permutations of genomic sequences create a library of new amalgamated sequences. These newly formed genomes can determine the fitness and survival of cells. In bacteria, homologous and non-homologous types of recombination lead to the evolution of new...
10.6K