Short RNAs in Stress and Longevity

My latest eBriefing for the New York Academy of Sciences covers a day-long May 12 meeting on "Short RNAs in Stress and Longevity." (The web publication was delayed by redesign and reorganization disruptions at the academy).

The sponsor, the Non-coding RNA Biology Discussion Group, used to call itself the RNA Interference Discussion Group. Its new name more accurately reflects the diverse regulatory and other roles of short RNAs. Many of these roles are far from being completely understood, and this meeting touched on several of them.

The combination of stress and longevity may seem like an odd pairing. But to the extent that many organisms have a built-in, switchable longevity program, stresses like starvation, which make living longer more attractive than reproducing, can activate it. The stress response is an entire field of its own, and stresses like heat shock are well known to produce major shifts in gene expression, inducing production of proteins like chaperones that help cells cope.

Frank Slack of Yale University and Ramanjulu Sunkar of Oklahoma State University explored two fields where researchers have extensively studied gene regulation by traditional protein-based mechanisms. For longevity in the worm C. elegans and for stress responses in plants, respectively, they saw the effects of naturally-occurring short RNAs (microRNAs and their plant relatives), and changed these responses by manipulating the short RNA levels. As in other fields, these studies are revealing a critical layer of gene regulation that has been overlooked until quite recently.

Germano Cecere works in the lab of Alla Grishok of Columbia University, who had found that short RNAs can regulate not just messenger RNA translation and degradation, but also its initial transcription from DNA. To find new examples, Cecere searched for short RNAs that are involved with chromatin remodeling, and identified many that play a role in stress and longevity.

Cells under stress often develop specialized complexes of proteins and RNA, known as stress granules, which may host some of the regulatory reactions or store low-priority messenger RNA. Anthony Leung of Phil Sharp's lab at MIT described how a particular polymer known for its role in DNA processes might act as a scaffold for these granules or even help regulate their activity.

Irina Groisman of the André Lwoff Institute dissected protein complexes that associate with the poly-adenylated tails found in mature messenger RNA. These complexes enforce the tradeoff between cellular senescence, which is related to longevity, and cancer.

Beyond the regulatory sequences that typically contain twenty-something bases, larger RNA can also process information on its own. Evgeny Nudler of NYU, who had identified riboswitches that respond to metabolites, described a different 600-nucleotide-long RNA that is the temperature-sensing element in the heat-shock response. This RNA sensor binds with the translational elongation factor eEF1A (which can also interact with non-heat stresses) to generate the response.

As this breathless summary hints, it's a challenge to combine such disparate topics into a coherent writeup. In this case, with just six talks, I gave up on aligning the talks into common themes and simply summarized each one separately. This diversity shows how wide open the field of RNA remains, going far beyond its traditional functions as messenger RNA, transfer RNA, and ribosomal RNA.