APOBEC- A KEY DEFENSE PROTEIN CAUSES CANCER
A recent study conducted by a team of Swiss and Russian scientists led by Sergey Nikolaev at the University of Geneva, Switzerland deciphered that APOBEC, a defense protein that usually functions as protecting agent against viral infection causes cancer in human beings.
APOBEC is a family of intrinsic cellular protein which has the power to modify a single-stranded DNA. Since the viral DNA is being frequently single stranded, the double stranded human DNA cannot be altered.
About 20% of APOBEC mutations arise due to abnormality in the DNA called "double-stranded breaks" where a part of the DNA is in a single-stranded state for a period of time causing multiple mutations. Researchers were able to govern the remaining 80% of APOBEC related mutations. They managed to identify in which direction the replication fork was travelling through the human cells. During the cell division process, the DNA replication starts at a specific location to produce two identical copies from the original DNA. The replication fork is caused by the separation of two original strands and synthesis of the new ones. DNA replication process is a dangerous mutagen when it takes advantage of a weakness during the DNA replication process thereby inducing mutations in our genome.
As a result, new strands are rebuilt as the fork moves along the chromosome. The two strands are replicated in two different mechanisms depending on the direction of the replication fork. Hence the reconstruction of strands is possible only when one of the them are constructed immediately.
Therefore, one strand i.e. the "leading strand" never exists as single stranded DNA whereas the other strand " lagging strand" continues to be single stranded for a period of time. Researchers were able to discover twice as many mutations on the "lagging strand" when compared with "leading strand". Findings suggested that APOBEC takes advantage of the DNA when "lagging strand" remains single and weak.
DNA replication process:
DNA replication process is a process of creating two identical replicas from the original DNA molecule which ensures that the next generation of cells contains the same genetic information.
It is one of the two strands which is oriented in 5' to 3' direction travelling towards the replication fork. It is synthesized continuously with no breaks in between.
It is a single stranded DNA replicated in 3' to 5' which moves away from the replication fork. It is synthesized discontinuously in fragments known as Okazaki fragments.
Okazaki Fragments is a relatively short fragment of DNA which is formed on the lagging template strand during the DNA replication process. In 1968, Reiji Okazaki, a pioneer Japanese molecular biologist along with his wife Tsuneko Okazaki and their colleagues discovered Okazaki fragments while conducting a research on replication of bacteriophage DNA in Escherichia coli.
Some of the encoding members of APOBEC protein family are mentioned below:
- APOBEC3G (A3G): is a single stranded DNA which acts as an effective cellular host defending agent prohibiting the expression of the functional form of the HIV encoded protein Vif. When this wild type of Vif attacks the A3G enzyme, all sorts of host defense advantage provided by A3G gradually diminishes and thereby promoting the emergence of new virulent strains of the HIV virus.A3G acts as a double agent in defense. It can either be an anti-viral factor capable of destroying the virus or it can help diversify viral genomes through gene mutation allowing the virus to be more resistant to drugs.To be more effective, the A3G should be incorporated into the virus.
- APOBEC-1 (A1): It is a cytidine deaminase which is linked with cholesterol control, cancer development and inhibition of viral replication. Levels of A1 is extremely low in the human liver and small intestine but higher in gastrointestinal epithelial cells. A1 is highly expressed in rodents with a wide tissue distribution.
- APOBEC 3A: It is a DNA cytidine deaminase commonly found in human beings, non-human primates and mammals containing antiviral effects. Studies suggests that APOBEC 3A can inhibit activity against parvoviruses, retroviruses, adeno associated virus (AAV), human T-cell leukemia virus type 1 (HTLV-1), foreign DNA and mobility of retrotransposons.
- Activation induced cytidine deaminase: AICDA is an enzyme which creates mutations in DNA by converting cytosine into uracil.
APOBEC Cytidine Deaminase and cancer:
DNA Cytidine deaminase APOBEC3B accounts for multiple human cancers. The researchers discovered that mutations induced by APOBEC3B can be found in many tumorous cells throughout the genome. There are presence of APOBEC mutation pattern in bladder, cervical, breast, head and neck, and lung cancers.