This post is based on speculation. It is an attempt at explaining the prevalence of mutations in cancer and their role in perpetuating the cancerous state.
The transcriptome of a cell may be classified into two sets: embryonic and adult. There are, of course, conserved elements that form a union of these sets but we are more interested in the embryonic transcriptome exclusive of the union.
We now consider the two Nucleotide Excision Repair (NER) mechanisms that have been studied to date: Global Genomic Repair (GGR) and transcription-coupled repair (TCR). Atanassov, et.al. A mutation can take place at or near an adult transcriptome and it is usually repaired by TCR. However, if a mutation takes place at an embryonic transcriptome during the adult stage, TCR can not repair it and, because it is in the adult, GGR may not be able to effect repairs. According to Lans et.al., "Intriguingly, in juvenile and adult animals TCR is the major NER pathway involved in the UV response. Analysis of the UV response of embryos shows that, during development, TCR gradually becomes more important than GGR."
We are now stuck with a mutation that perpetuates. CRF theory (our theory of cancer initiation) now says that the embryonic transcriptome will be activated and therein is a mutated gene that could increase the cancer cell's survival. I surmise that mutated genes playing a dominant role in cancer do not play a role unless and until the embryonic transcriptome is activated--they are dormant in the adult cell with a correct physiome.
TCR is thought to take place when RNA polymerase II "stalls." If there is no similar NER mechanism in place in the adult replicating cell, the mutation may perpetuate itself. It may be that DNA Replicase, unlike RNA Polymerase II, is capable of attempting a "best fit" in the absence or impairment of a GGR mechanism but this is purely speculative on my part.
[In researching this blog I noted that bacteria do not have histones while eukaryotes do. Could it be that histones evolved not only to pack the DNA but to also minimize mutation? Bacteria need mutations because they are subjected to vastly more diverse environments than are multicellular organisms.]
The transcriptome of a cell may be classified into two sets: embryonic and adult. There are, of course, conserved elements that form a union of these sets but we are more interested in the embryonic transcriptome exclusive of the union.
We now consider the two Nucleotide Excision Repair (NER) mechanisms that have been studied to date: Global Genomic Repair (GGR) and transcription-coupled repair (TCR). Atanassov, et.al. A mutation can take place at or near an adult transcriptome and it is usually repaired by TCR. However, if a mutation takes place at an embryonic transcriptome during the adult stage, TCR can not repair it and, because it is in the adult, GGR may not be able to effect repairs. According to Lans et.al., "Intriguingly, in juvenile and adult animals TCR is the major NER pathway involved in the UV response. Analysis of the UV response of embryos shows that, during development, TCR gradually becomes more important than GGR."
We are now stuck with a mutation that perpetuates. CRF theory (our theory of cancer initiation) now says that the embryonic transcriptome will be activated and therein is a mutated gene that could increase the cancer cell's survival. I surmise that mutated genes playing a dominant role in cancer do not play a role unless and until the embryonic transcriptome is activated--they are dormant in the adult cell with a correct physiome.
TCR is thought to take place when RNA polymerase II "stalls." If there is no similar NER mechanism in place in the adult replicating cell, the mutation may perpetuate itself. It may be that DNA Replicase, unlike RNA Polymerase II, is capable of attempting a "best fit" in the absence or impairment of a GGR mechanism but this is purely speculative on my part.
[In researching this blog I noted that bacteria do not have histones while eukaryotes do. Could it be that histones evolved not only to pack the DNA but to also minimize mutation? Bacteria need mutations because they are subjected to vastly more diverse environments than are multicellular organisms.]
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