Monday, January 7, 2013

Genetic and Epigenetic Mechanisms in metal carcinogenesis (2 of x in a series)

Part One in the series can be found here:

Background  Part Two:

There are 3 areas that can be affected by metals in cancer forming processes:

(1) DNA damage

DNA damage, due to environmental factors and normal metabolic processes inside the cell, occurs at a rate of 1,000 to 1,000,000 molecular lesions per cell per day.[1] While this constitutes only 0.000165% of the human genome's approximately 6 billion bases (3 billion base pairs), unrepaired lesions in critical genes (such as tumor suppressor genes) can impede a cell's ability to carry out its function and appreciably increase the likelihood of tumor formation.

The vast majority of DNA damage affects the primary structure of the double helix; that is, the bases themselves are chemically modified. These modifications can in turn disrupt the molecules' regular helical structure by introducing non-native chemical bonds or bulky adducts that do not fit in the standard double helix

There are five main types of damage to DNA due to endogenous cellular processes:
  1. oxidation of bases [e.g. 8-oxo-7,8-dihydroguanine (8-oxoG)] and generation of DNA strand interruptions from reactive oxygen species, [From Connie: I have written extensively on this in the blog.  You can type in: Reactive oxygen species (ROS) in the blog search box and a list of posts will appear.  likewise, you can find posts under oxidation and  oxidative stress.]
  2. alkylation of bases (usually methylation), such as formation of 7-methylguanine, 1-methyladenine, 6-O-Methylguanine
  3. hydrolysis of bases, such as deamination, depurination, and depyrimidination.
  4. "bulky adduct formation" (i.e., benzo[a]pyrene diol epoxide-dG adduct, aristolactam I-dA adduct)
  5. mismatch of bases, due to errors in DNA replication, in which the wrong DNA base is stitched into place in a newly forming DNA strand, or a DNA base is skipped over or mistakenly inserted.
DNA damages in frequently dividing cells, because they give rise to mutations, are a prominent cause of cancer.

(2) Epigenetic changes

At its most basic, epigenetics is the study of changes in gene activity that do not involve alterations to the genetic code but still get passed down to at least one successive generation. These patterns of gene expression are governed by the cellular material — the epigenome — that sits on top of the genome, just outside it (hence the prefix epi-, which means above). It is these epigenetic "marks" that tell your genes to switch on or off, to speak loudly or whisper. It is through epigenetic marks that environmental factors like diet, stress and prenatal nutrition can make an imprint on genes that is passed from one generation to the next.

Epigenetic changes represent a biological response to an environmental stressor. That response can be inherited through many generations via epigenetic marks, but if you remove the environmental pressure, the epigenetic marks will eventually fade, and the DNA code will — over time — begin to revert to its original programming.

(3) Activated cellular signalling

Cell signalling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue homeostasis. Errors in cellular information processing are responsible for diseases such as cancer, autoimmunity, and diabetes. By understanding cell signaling, diseases may be treated effectively and, theoretically, artificial tissues may be created.

I will run part three tomorrow.

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