PrimPol - An Enzyme That Heals DNA

DNA is the treasure trove of genetic information. It is basis of our existence and is responsible for passing on information from one generation to another. DNA is present in all cells of our body and these cells are continually multiplying to regenerate injured tissue and heal injuries. This cell multiplication also involves replication of the DNA molecules. Thus each new daughter cell contains a replica of the DNA present in the parent cell. But with time this stable DNA molecule undergoes damage and if these damages are not repaired then they will be transferred to the next generation of daughter cells. DNA damage can occur due to replication errors, exposure to UV radiation and exposure to mutagenic chemicals. If DNA damages are not repaired the cell might enter a senescent state and initiate self destruction in the form of apoptosis. DNA damage can also lead to the cell modifying into a cancerous cell. Thus, it is of utmost importance to repair these DNA damages.

DNA polymerase is the principal enzyme which is responsible for replication of DNA by formation of a replication fork when the two DNA strands separate. It works upon short primer segments of nucleotides and adds complementary bases to generate an entire DNA molecule. In case of a break in the DNA, the enzyme skips the damaged region and replicates to form a daughter DNA molecule with a break in it. This could lead to genomic instability and harmful mutations. This damage should be repaired post-replication be DNA primase enzymes. These enzymes can form DNA segments from broken fragments of DNA and can help seal the gap created.

PrimPol is the latest primase enzyme that has been coded from the human genome and it has the unique property of being both a polymerase and a primase. Proteins related to PrimPol have been found in archaebacteria which are the oldest known living form on Earth. PrimPol is present in the nucleus but it can also be found in larger quantities in the mitochondria. It very recently has been described and and its functions characterised in a publication by Sara Garcia-Gomez et al. in the leading journal Molecular Cell (http://download.cell.com/molecular-cell/pdf/PIIS1097276513007442.pdf?intermediate=true).

It has been proposed that PrimPol has adapted to producing normal DNA molecules from damaged sequences which were produced due to the adverse and DNA-damage prone environment present on primitive Earth. The survival and evolution of archaebacteria, even in the high temperature and saline conditions present, can be attributed to this miracle enzyme. Thus, PrimPol can heal and repair broken DNA fragments. It shows high specificity and efficiency when replicating damaged DNA strands.

Studies conducted by Prof. Luis Blanco at CSIC (Spanish National Research Council), Madrid have shown that PrimPol is an efficient primase as well as polymerase enzyme. Conventional polymerase enzymes require primers in the form of short nucleotide sequences to start the replication process. PrimPol can read and generate DNA strands without the need for the presence of random primer fragments. In cases of replication of damaged DNA, it skips over these fragments during replication and afterwards repairs the breaks by putting in the missing fragments. Thus, PrimPol prevents any lethal mutation or damage that may occur if the broken DNA is not repaired. DNA damage has been held responsible for several physiological conditions like ageing, neurodegeneration and even cancer.

Prof. Luis Blanco has quoted, "I am convinced that this fantastic enzyme will open numerous novel applications in the field of molecular biology, some of them we can only hint at this moment given the highly innovative potential of its key features." This potential has already been understood by investigators at SYGNIS AG, a leading pharmaceutical with offices in Spain and Germany. They have started developing a thermostable version of the enzyme which would utilise all its properties for greater industrial benefit.

• PrimPol has the capability of replicating RNA as well and can be used for RNA amplification procedures which would be very viable for the present biotechnological market.
• PrimPol would be very useful for laboratory, forensic and other experimental purposes where DNA samples are stored in conditions which might cause damage to the DNA. Thus, it can handle such damaged templates which cannot be worked upon by the current amplification procedures.
• PrimPol also has a role in multiple displacement amplification (MDA) reactions and can generate primers for use by other DNA polymerases. This prevents the use of synthetic primers and results in a more specific and uniform amplification of DNA.
• The ability of PrimPol to introduce a variety of nucleotide substrates into the DNA template can be utilised to produce combination nucleotides like fluorescent DNA molecules.

The advent of thermostable PrimPol enzyme would revolutionise the biotechnological market and research scenario. SYGNIS AG is in the final characterisation and processing stages. Though its patent protection is still pending but the company is in talks with other pharmaceutical and biotechnological giants for out-licensing the product and launching it as soon as possible.

The latest discovery of this enzyme, PrimPol is a breakthrough research. It can change the face of the modern day biotechnological procedures. It can also be utilised as a therapeutic agent for treatment of diseases which occur due to DNA destruction. These diseases range from skin damage to ageing to even cancer. Its property of healing DNA lesions has a vast applicability and the future is very bright for this discovery.

References (additional)

• Silvana Mouron, Sara Rodriguez-Acebes, Maria I Martinez-Jimenez, Sara Garcia-Gomez, Sandra Chocron, Luis Blanco, Juan Mendez. Repriming of DNA synthesis at stalled replication forks by human PrimPol. Nature Structural & Molecular Biology, 2013; DOI: 10.1038/nsmb.2719
• http://www.sygnis.com/notas-de-prensa/2013-2/molecular-cell-publishes-the-discovery-and-characterization-of-primpol-a-new-type-of-human-dna-polymerase/
• http://www.cell.com/molecular-cell/abstract/S1097-2765(13)00744-2
• http://www.sygnis.com/primpol/#



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