mRNA structures translationally prefered by cancer

Translation initiation is often over-activated in cancer cells, however, this over-activation does not favour mRNAs equally. In fact it seems translation over-activation favours mRNAs that promote tumourgenesis and tumour progression. Santhanam et al. in PLoS ONE recently took a look at what general mRNA structural characteristics determine translational activity in cancer cells with over-activated translation initiation. Previously lots of focus has been on the influence of secondary structure and length of the 5'UTR as this has been demonstrated to influence 'translatability'. With new information about microRNAs binding to the 3'UTR to influence translation, an unbiased approach to evaluate their relative influence seems like a very good idea. The methods in this work essentially involved comparing microarray analysis of cell lines with over-activated translation initiation and those without. In each cell line the translational activity of each message was determined by quantification of the percentage of the message that was being actively translated. Then they looked for commonalities in the sequence of the mRNAs that are specifically translationally activated by translational over-activation. (probably using computers) :) Massive data set and unbiased approach = pretty convincing coorelations (we're talking p values of 10E-6)

Here is what cancer cells look for in a potentially translatable mRNA:
1. GC rich 3'UTR
2. secondary structure involving sequences JUST before the start codon and JUST after the stop codon. These results are more striking for the 3'UTR.
3. Short 3'UTRs
4. No microRNA target sites. Indeed the presence of predicted microRNA target sites was negatively coorelated with translational over-activation. (with some exceptions)

The take home message is, somewhat surprising, that the 5'UTR is less correlated with effects on translation over-activation relevant to cancer than the 3'UTR.

Malignancy from organ transplants?

I've always wondered about this: Is it possible to get cancer from a donated organ? In theory the organs are inspected and come from healthy donors, but microscopic lesions would be undetectable. Furthermore, the recipients are on immune suppressants, making the cancer even more likely to develop. In fact it's a common occurrence in recipients to develop de-novo tumours after transplantation, but it's usually from their own tissue and a direct result from the drugs. For example, melanomas are 1.6-2.5 times more likely in the transplant population. Well a story this week explains how a 15y old boy who was mis-diagnosed with meningitis but who in fact had lymphoma, ended up causing the death of 2 of the four recipients of his tainted organs. The other two had the organs removed and are undergoing chemo. I wonder if they have improved chances of survival once they are off the immunosuppressants since the cancers are mismatched or whether the match required for transplantation is close enough for the tumour to behave like a de-novo host tumour... The Lancet has a great review on how to threat both types of malignancies:

"Transmission of an undetected tumour in the donor is rare (incidence 0·02%).⁷⁷ The question of whether a tumour in the recipient has arisen de novo or by transmittance from the donor can be answered by doing a biopsy of the tumour and cross karyotyping the recipient and donor tissue to establish tumour origin. [...] The overall mortality from donor-related malignancies is calculated at 38%, with that of transmitted tumours at 46% and derived de-novo tumours at 33%. Cadaveric-donor-related tumour mortality is 0·007% (8 of 108 062 recipients).⁷⁷"

Holy Freaking Heterogeneous Ribosomes!

Once again I have Palazzo to thank for pointing out a cool paper - this one from Pam Silver's lab, showing that different paralogous (duplicated) yeast ribosomal proteins are involved in translating different messenger RNAs. Since there are some 60 or so duplicated ribsomal proteins, this suggests a huge possible amount of ribosomal heterogeneity in the cell. Ribosomes are not all the same - even in basic subunit structure -and this might be an important piece of the translational regulation puzzle. The authors go on to point out the parallels between this situation and that of histone proteins, which can also bind nucleic acid, are also highly duplicitous in yeast, and also highly subject to regulation through post-translational modification. Thus they propose that if there's a "histone code" that regulates transcription, there may also be a "ribosome code" that regulates translation. Personally, I don't see the evidence that either sort of code exists (vague speculation about codes usually strikes me as an easy way to score sexy points), but there's certainly something interesting going on here.

More interestingly, we recently had a great journal club about the evolution of paralogous histone-modifying enzymes in yeast. The paper examined the evolutionary balance between redundancy and diversity of function in duplicate gene pairs, and showed that functionally distinct (non-redundant) paralogues can compensate for their partner when, and only when, the other is deleted. Presumably then, a similar evolutionary dynamic could be at play in the evolution of ribosomes and the regulation of translation in general.

Speaking of histones, if there's no such thing as histone code, maybe it's more of a universe. The complexity of chromatin structure is unbelievable. What's even cooler is that it's dynamic. So not only is chromatin complex, it's ALIVE. At least that was the impression I took away from a recent talk by Ottawa chromatin mapper Marjorie Brand. Check out her lab's latest paper on how spreading of chromatin-associated MLL protein mediates communication between a distal upstream activator element and the B-globin promoter during differentiation.

Another random factoid that was mentioned in the first paper, and news to me: the yeast (S. cerevisiae) arose from a massive whole-genome duplication, but eventually all but 10% of duplicated genes were lost. Weird. Was the initial duplication event selection-neutral for the original yeast cell it occurred in? Hard to imagine, since I would think two genomes take longer to replicate than one, not to mention the structural instability associated with having all that homologous DNA around. So what's the advantage? Not much, if most duplications were eventually lost. Doesn't this say there was indeed a fitness cost to having extra copies of all those genes if they were ultimately weeded out by selection? The only thing that makes sense to me is if the cost/benefit of duplicate genes has varied over yeast evolutionary time. So it was advantagenous to have backup gene copies back sometime in ancient history, but then became unnecessary or cumbersome more recently. Maybe the environment or the yeast's response to it changed. For example, maybe at one point gene inactivation via radiation-induced DNA damage was a big problem for yeast, so it was often useful to have a backup genome copy around. Then, either environmental radiation diminished or yeast evolved a system for preventing or repairing DNA damage, and they no longer needed to keep the backup genes around. I suppose another possibility is that it has something to do with the role of sexual reproduction..........

Alas, I rant like a raving lunatic. Someone set me straight.

Mitochondrial Madness

Our often-neglected bacterial endosymbionts the mitochondria seem to have their fingers in all aspects of eukaryotic cell functioning. Not only do they make us ATP and tell our cells when to die, they even have their own genome, which they can replicate, transcribe and translate all on their own. But mitochondria don't just use proteins encoded in their own genomes; they've also got some out on loan from the nucleus. And this is where the madness begins. Somehow this excellent Molecular Cell review on mitochondrial transcription found its way onto my lab bench, so I read it. Here are a few of the mind-blowing facts you can discover therein:

• The eukaryotic single-subunit mitochondrial RNA polymerase was ganked from bacterial viruses (bacteriophage T3/T7), and has no relation to those encoded by bacteria themselves.

• Even weirder, the phage-like mtRNA polymerase is encoded in the nuclear genome of eukaryotes. Interstingly, an isoform of mtRNA polymerase lacking a mitochondrial localization signal performs transcription of nuclear-encoded genes in the nucleus (RNA pol IV).

• The amino-terminal domain of yeast mtRNA polymerase has diverged from its phage ancestry, and has evolved to mediate coupling between mitochondrial transcription and translation. In fact, mutations in the ATD lead to deficiencies in mitochondrially-encoded OXPHOS enzymes and thereby decrease lifespan in yeast.

• What? Mitochondrial translation? What's up with that? Nobody really knows...

Also, check out this wicked album of artistic renditions of cells by Gary Carlson which I ganked the above photo from. Nice job Gary!