ENCODE logo Not long ago there was some keruffle over the ENCODE data,1 and the unrelated but almost simultaneous Cell paper,2 that demonstrated widespread transcription even from apparently-inactive genes — for example, this discussion and this one at Ars Technica’s Nobel Intent , and this one at Sandwalk. The observations were considered surprising because RNA was (and is) usually considered to be fairly tightly regulated. The ENCODE data, in particular, were used as arguments pro and con “junk” RNA — non-functional transcription.

The presence of non-functional RNA, though, didn’t strike me as very surprising at all, and part of the reason for that was that I had been primed to think about efficiency in cellular processes by Jon Yewdell’s “DRiPs” hypothesis.3

Briefly (I want to talk about DRiPs in detail some other time) Yewdell suggests that peptides that are presented on MHC class I to cytotoxic T lymphocytes are usually derived, not from full-length, functional proteins, but from “defective ribosomal products” — proteins that began translation and got screwed up partway through, or that completed translation and failed to fold properly. Proteins, in other words, that were defective from the get-go, that never had a chance to contribute to the whole happy economy of the cell. This contrasts to the traditional view, that antigenic peptides are derived from proteins during their normal turnover, often over a period of many hours.

Pollock Untitled (Green Silver)
Pollock’s drips: “Untitled (Green Silver)”

Yewdell argued that in fact a large percentage of translation (he’s offered various percentages, but let’s say 30% of translation) ends up in this defective pool, and because it’s defective it’s destroyed very rapidly by the proteasome — again, he’s offered various numbers, but let’s say for the sake of argument that it’s destroyed within a handful of minutes.

I don’t mind saying that I was extremely skeptical when I read his initial paper, and I am still quite skeptical about the overall contribution; but over the years I have (reluctantly) come a long way to accepting the general principle. But — unlike many of the people who disagreed with the DRiP hypothesis — I didn’t find the principle of DRiPs per se implausible.

In fact, it was one of those things that I had never thought of, but that made immediate sense to me as soon as I read the idea. I think of it as an information theory thing: Preventing errors in translation must take a certain amount of energy; at some point the incremental energy needed to reduce the error rate from N to N-1 would be greater than the amount of energy needed to degrade a defective product. And as soon as you consider it as that equation, it becomes a slider, and the set-point could be almost anywhere. It’s quite plausible (to me, anyway) that the amount of energy used in error prevention is relatively high, whereas the energy loss in protein degradation is relatively low — and so it’s cheaper, energetically, to simply make error-riddled protein, and let the proteasome sort it out after the fact.

(I’m simplifying all the arguments here, pro and con. I’ll probably take them up in bits and pieces later on.)

Anyway, exactly the same reasoning applies to transcription. The amount of energy that it would take to clamp down and make absolutely perfect identification of proper transcriptional start sites, must at some point be greater than the amount of energy involved in destruction of aberrant RNA. So this is why I thought it was quite predictable that there would be widespread, low-level, transcription of non-functional RNA that would then run into the next level of information processing.

Blogging on Peer-Reviewed ResearchThe reason I thought about this today, months after the fuss has pretty much died down, is a paper from Nilabh Shastri’s group4 that demonstrates another instance of what, I suspect, is another example of aberrance that’s tolerated by cells. (There’s also a commentary on the paper,5 by Yewdell.) Today’s post was in fact supposed to be entirely about that paper, but what with all the time I’ve spent blathering about the background, I’ll finish up with a new post later this week. In any case it’s time for me to go read “Green Eggs and Ham” to my kids.

(I’m trying out including the BPR3 icon here. I’m not entirely convinced by the BPR3 rationale, but I’m willing to see what happens for a while, anyway.)

  1. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 2007 447, 799-816. []
  2. Guenther, M. G., Levine, S. S., Boyer, L. A., Jaenisch, R., and Young, R. A. (2007). A chromatin landmark and transcription initiation at most promoters in human cells. Cell 130, 77-88.[]
  3. Yewdell, J. W., Aton, L. C., and Benink, J. R. (1996). Defective ribosomal products (DRiPs): A major source of antigenic peptides for MHC class I molecules? J. Immunol. 157, 1823-1826.[]
  4. Maness, N. J., Valentine, L. E., May, G. E., Reed, J., Piaskowski, S. M., Soma, T., Furlott, J., Rakasz, E. G., Friedrich, T. C., Price, D. A., Gostick, E., Hughes, A. L., Sidney, J., Sette, A., Wilson, N. A., and Watkins, D. I. (2007). AIDS virus specific CD8+ T lymphocytes against an immunodominant cryptic epitope select for viral escape. J Exp Med 204:2505-2512 []
  5. Yewdell, J. W., and Hickman, H. D. (2007). New lane in the information highway: alternative reading frame peptides elicit T cells with potent antiretrovirus activity. J Exp Med 204:2501-2504 []