JUL 31, 2018 5:45 PM PDT

Protein Regulation of DNA Replication in Cancer Cells - A New Early Target for Broad Therapeutics?

WRITTEN BY: Mauri Brueggeman

Researchers have been examining the loss of control over the DNA replication and cell proliferation process since it was connected to the development of cancer.  One of the most well-known and common traits of the disease in all types of cancer diagnoses is this this uncontrolled cellular replication and growth. 

In healthy cells, this process is carefully regulated and controlled through pathways and cellular checkpoints.  In a Nature Communications article published July 17, 2018, researchers identified a replication initiation determinant protein (RepID) that regulates replication through association of other proteins, drawing them directly to chromatin sites for replication initiation.  One of these proteins is a Culling-RING E3 ubiquitin ligase (CRL) which one of many CRLs.  CRL4 is recruited by RepID to chromatin in the very early stages of mitosis (cell cycle) prior to replication.  CRL4 acts to degrade CDT1, a protein that promotes replication at the appropriate time in the cell cycle.  Loss of CDT1 is the switch that tells a cell to only begin the DNA replication cycle once.  In addition to CRLs, a complex called SCF is also part of the cell cycle progression in mammals.  It, too, can facilitate degradation of chromatin proteins involved in regulation of mitosis and DNA replication later in the cell cycle (the S-phase).

In cases of RepID loss of expression or function, turning off that CDT1 switch is up to the SCF complex later in the cell cycle.  However, because the degradation was originated after DNA replication began, the cell re-replicated its DNA because there were higher levels of CDT1 associated with the chromatin.

Part of the SCF complex is a protein called SKP2.  This group of researchers treated the depleted RepID cancer cell cultures with a drug that inhibits SKP2, known as SZL-P1-41.  Their findings indicated that cells expressing intact RepID were not affected by the SKP2 inhibitor but cells with no RepID showed high sensitivity to SKP2 inhibition. The RepID knockout cells entered apoptosis and there were no surviving colonies in cell culture.  The researchers conclude that, “RepID expression levels might modulate the sensitivity of cancer cells to cullin-targeting drugs.”

Sources: Nature Communications, National Cancer Institute,

About the Author
  • Mauri S. Brueggeman is a Medical Laboratory Scientist and Educator with a background in Cytogenetics and a Masters in Education from the University of Minnesota. She has worked in the clinical laboratory, taught at the University of Minnesota, and been in post secondary healthcare education administration. She is passionate about advances and leadership in science, medicine, and education.
You May Also Like
MAY 02, 2020
Cancer
MAY 02, 2020
Tracking DNA Methylation as a Prognostic Marker
In the modern age of biological research, one of the tools that have become readily available in the ever-increasing dat ...
MAY 04, 2020
Cancer
MAY 04, 2020
A Retroactive Study Finds an Immunotherapy Effective as a Third-Line Therapy
Cancer is a particularly persistent disease. Many therapies are composed of one or more different treatments. These trea ...
MAY 09, 2020
Cancer
MAY 09, 2020
Examining a Combination Therapy Against Gastric Cancer
Often when it comes to treatments for cancer, designing or discovering new leads can take years. One of the common pract ...
MAY 26, 2020
Cancer
MAY 26, 2020
Does having a child with cancer increase parents' risk of divorce?
A study from Denmark published in the American Cancer Society journal CANCER reports that having a child with cancer doe ...
JUN 01, 2020
Cancer
JUN 01, 2020
A New RNA in Fine-Tuned Signal Regulation
In a healthy cell, many complex networks work to make sure everything runs as it should. Some of these networks function ...
JUN 08, 2020
Cancer
JUN 08, 2020
Using Soft Tissue Sarcoma's Immune Defense as a Biomarker
Programmed cell death protein 1 (PD-1) has been a big player in the treatment of both autoimmune disease and cancer. PD- ...
Loading Comments...