Debunking myths on genetics and DNA

Musings on writing, genetics and photography. My debut novel CHIMERAS, a hard-boiled mystery with a genetic twist, is now available on Amazon.

Sunday, August 18, 2013

Is there such thing as over-editing?

 A while ago I wrote a post based on JS Mattick's work [1] on RNA editing, the introduction of changes in RNA molecules after they have been translated from a gene. This kind of editing confers a certain adaptability to the protein without changing the gene that codes for it. Bacteria and viruses, for example, undergo extensive RNA editing in order to constantly re-adapt to the host's immune response. In eukaryotes RNA editing is rarer, but it still happens and is involved in many epigenetic mechanisms. It is also important in the immune system, as successful immune responses are driven by a great adaptability to new invaders.

RNA editing can be obtained through the insertion of one or more nucleotides, or the opposite, the deletion of one or more nucleotides. It can also be obtained by changing a single nucleotide in a certain motif, which is carried on by special enzymes. One family of such special enzymes is the APOBEC family, some of which have an important role in defending us from retroviruses, the viruses that carry RNA.

This is how APOBEC3 enzymes operate: in order to reproduce, the retrovirus transforms its RNA into single stranded DNA and then uses an enzyme to insert its DNA into the cell's DNA. Once there, the virus will reproduce using the cell's own duplication mechanisms. That's when the APOBEC enzymes get into action, by inducing a number of mutations in the viral DNA that end up deactivating it.

So, these APOBEC enzymes are the good guys, right?

Alexandrov et al. found out that they may not be, as they explain in a recent Nature paper [2].

The authors' objective was to characterize somatic mutations in cancer tissues. As you know, cancer originates from cells with anomalies in their DNA. Some anomalies are present from birth, though the vast majority accumulate as we age, some caused by external agents known to disrupt cell regulation and DNA's ability to self-repair. Other mutations appear randomly as cells undergo cellular division. As the authors say, "different mutational processes often generate different combinations of mutation types, termed signatures." Characterizing the "mutational signatures" that are associated with cancer can help us understand the mechanisms that drive cancer growth and pave the road to better ways to target and/or prevent the disease.

Here's a summary of what the researchers found:
"We compiled 4,938,362 somatic substitutions and small insertions/ deletions (indels) from the mutational catalogues of 7,042 primary cancers of 30 different classes (507 from whole genome and 6,535 from exome sequences). In all cases, normal DNA from the same individuals had been sequenced to establish the somatic origin of variants. The prevalence of somatic mutations was highly variable between and within cancer classes, ranging from about 0.001 per megabase (Mb) to more than 400 per Mb. Certain childhood cancers carried fewest mutations whereas cancers related to chronic mutagenic exposures such as lung (tobacco smoking) and malignant melanoma (exposure to ultraviolet light) exhibited the highest prevalence [2]."

In order to catalogue the somatic changes driven by cancer, the researchers harvested both healthy and cancerous cells and compared the latter to the former. The healthy DNA was used as a reference and mutations away from this references were assumed to have originated from the disease. They compiled a list of all mutations that were statistically associated to cancer and looked at the biological pathways/mechanisms these mutations affected.

The finding that childhood cancers carried less mutations is not too surprising since cellular lineages are younger. I'm also speculating that childhood cancers are more likely to be caused by underlying genetic anomalies, maybe combined by additional somatic mutations, but since they appear earlier in life, they probably require less somatic mutations to be triggered.

Alexandrov et al compiled a table of the 21 most observed signatures across the 30 different classes of cancers and then tested them for possible statistical associations. The most common signature (60% of cancers) was associated with age. Others were associated with smoking, UV light, BRCA1/2, etc. But here's what I found surprising: two of those signatures, present in 14.4% and 2.2% of cancers respectively, were associated with APOBEC.
"On the basis of similarities in mutation type and sequence context we previously proposed that signature 2 is due to over activity of members of the APOBEC family of cytidine deaminases, which convert cytidine to uracil, coupled to activity of the base excision repair and DNA replication machineries. [. . .] However, the reason for the extreme activation of this mutational process in some cancers is unknown. Because APOBEC activation constitutes part of the innate immune response to viruses and retrotransposons it may be that these mutational signatures represent collateral damage on the human genome from a response originally directed at retrotransposing DNA elements or exogenous viruses. Confirmation of this hypothesis would establish an important new mechanism for initiation of human carcinogenesis [2]."
I found this extremely intriguing. What causes the over-expression of the APOBEC enzymes in cancer tissue? We know these enzymes become activated in response to a retroviral infection, could their over-expression be the aftermath of a viral infection, then? And then their over-activation led to over-editing and hence DNA damage? Would it be at all possible that the DNA damage that led to cancer came first instead, and then the APOBEC enzymes became activated at a later stage as an attempt from the immune system to get rid of the cancerous cells?

Clearly, more studies are needed to find the answer. A complete list of mutational signatures in cancer should be compiled and compared to known models of DNA mutagens and perturbations of the cell-repair machinery. But such list should also be correlated with the biological characteristics of each cancer, the pathways and molecular mechanisms they interact with, and of course the epidemiological changes they may induce.

[1] Mattick JS (2010). RNA as the substrate for epigenome-environment interactions: RNA guidance of epigenetic processes and the expansion of RNA editing in animals underpins development, phenotypic plasticity, learning, and cognition. BioEssays : news and reviews in molecular, cellular and developmental biology, 32 (7), 548-52 PMID: 20544741

[2] Ludmil B. Alexandrov, Serena Nik-Zainal, David C. Wedge, Samuel A. J. R. Aparicio, Sam Behjati, Andrew V. Biankin, Graham R. Bignell, Niccolò Bolli, Ake Borg, Anne-Lise Børresen-Dale, Sandrine Boyault, Birgit Burkhardt, Adam P. Butler, Carl et al. (2013). Signatures of mutational processes in human cancer Nature DOI: 10.1038/nature12477

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