Cancer Initiation: Circumstancial evidence for an epigenetic checkpoint in the cell cycle

Tuesday, February 7, 2017

Circumstancial evidence for an epigenetic checkpoint in the cell cycle

Introduction

   We have introduced the concept of a checkpoint in the cell cycle, which prevents premature progression of the cell cycle, that is, cell division or mitosis before a new copy of DNA has been completed. At the present time, checkpoints have only been considered with respect to DNA sequence completion, not duplication of the appropriate epigenetic marks, alternately referred to as methylation of the CpG islands. This duplication of methylation process is called "maintenance", and is mediated by the primary maintenance DNA methyl-transferase, DNMT1.

The case of vitamin b12 deficiency


   It is now known that the cell cycle can be blocked in prospective blood cells ( megaloblasts) by a deficiency in vitamin b12. The condition is known as megaloblastic anemia and is described below, or in the first reference . [1] 


From the wikipedia entry on megaloblastic anemia :
 Megaloblastic anemia (or megaloblastic anaemia) is an anemia (of macrocytic classification) that results from inhibition of DNA synthesis during red blood cell production.[1] When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis (M) stage. This leads to continuing cell growth without division, which presents as macrocytosis.
 

Why would b12 deficiency inhibit DNA synthesis?

 
  Vitamin b12 has two known functions, or pathways in the body. In relation to the citric acid cycle, ( also called the Krebs cycle ), vitamin b12 mediates the conversion malonal CoA to succinal CoA.  Succinal Coenzyme A is an intermediary in the Krebs cycle, and can go on to function in the production of ATP.
   The other function of b12 is in the Single Carbon Metabolism pathway. In relation to this pathway, b12 is necessary for the production of SAM and glutathione.  In turn, glutathione deficiency is known to impact DNA methylation. [2]

Bingo!

Even though we have never heard of b12 being a factor in the production of DNA, it is a factor in methylation of CpG islands, or promoters, associated with a cells differentiation. We now have a connection between a new prospective checkpoint type mechanism and a potential factor in cancer and other diseases, that is b12 deficiency.

Discussion


   If in fact there is some mechanism that could be called a checkpoint, then loss of this mechanism could be considered a new source of cancer causation. We know that single nucleotide polymorphsms associated with single carbon metabolism may be significant in increasing risk of caner.  Perhaps this epigenetic checkpoint is active in stem cells which are dividing in environments that are immunologically privileged. Such is the case in bone marrow.


Conclusion


   After consideration of some other types of cells, I am going to go out on a limb and say that the epegenetic checkpoint is not a universal feature of cells. In some cells, such as in the hematopoetic ( blood generation ) system, b12 blocks cell cycle progression because of epigenetic failure associated with the function of DNA methyl-transferase,    DNMT1.

References


[1] Emmanuel Andres, and Khalid Serraj  Optimal management of pernicious anemia J Blood Med. 2012; 3: 97–103.[PubMed Central]

[2]  Lertratanangkoon K, Wu CJ, Savaraj N, Thomas ML.    Alterations of DNA methylation by glutathione depletion. Cancer Lett. 1997 Dec 9;120(2):149-56. [Abstract]


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