Biologjia Online

Approximately 60% of human genes undergo alternative splicing. This alternative splicing allows a single gene to encode dozens, and in some cases even thousands, of different protein isoforms, vastly increasing the diversity of the proteome that can be encoded by a limited number of genes. In mammals, only a fraction of the regulatory proteins (splicing factors) involved in controlling alternative splicing have been identified, and little is known about the mechanisms by which these factors regulate splicing. In this paper, Naganari Ohkura and colleagues identify an enzyme called coactivator-associated arginine methyltransferase 1 (CARM1), which is known to contribute to transcriptional activation by methylating histone H3, as a regulator of alternative splicing.

Ohkura and colleagues offer two novel observations about CARM1: 1) they identify new splicing variants of CARM1, which are expressed in a tissue-specific manner, and 2) they report the exciting discovery that one of the new splicing variants, CARM1-v3, binds to the U1 small nuclear ribonucleoprotein particle (snRNP) component of the spliceosome and alters splicing patterns of mRNAs. Interestingly, a C-terminal CARM1-v3 region, which is unique to this particular splice variant, is responsible for the splicing regulation function, whereas the methyltransferase activity of CARM1 is dispensable. These findings add CARM1 to the list of components that can modulate 5' splice site selection and provide a new mechanism by which transcription and processing, two critical steps in gene expression, may be coordinated.

Nat. Genet. 10.1038/ng1608 (2005). Genetically identical organisms that have been raised in identical environments age at different rates, suggesting that in addition to genes and environment, chance physiological phenomena can influence life span. Rea et al. report that the stress response system of Caenorhabditis elegans is subject to an underlying physiological randomness that affects how it copes with environmental insults. They placed the gene encoding green fluorescent protein (GFP) under the control of the regulatory region from the gene encoding a heat shock protein, creating an easily scored biomarker. Upon exposure to heat, isogenic worms exhibited considerable variation in fluorescence, and those expressing the highest amount of GFP tolerated heat the best and lived the longest. The physiological state indexed by GFP expression level was not heritable, and the authors suggest that stochastic variation in molecular and biochemical reactions could account for the variation in individual robustness and longevity. -- LDC

The cellular mechanisms for dealing with nutritional stress are remarkably conserved, with the same signaling network used in organisms from yeast to mammals. In one sense, this is not terribly surprising since the most pressing response to such potential injury is always the same: suppress those biochemical reactions that consume energy while at the same time triggering those metabolic pathways most effective at generating ATP. But an interesting problem to contemplate is how this fundamental process has been adapted to the complexities of a multicellular organism in which recognition of the nutritional state is frequently provided by more subtle cues such as hormones or impulses generated within the central nervous system. Moreover, although the cellular responses to nutrient deprivation are conserved phylogenetically, organismal reactions in metazoans are more multifaceted in that one organ often sacrifices for the good of the whole. The major phylogenetically conserved pathway for signaling nutritional stress is now well established as centering on the protein kinase Snf1 in budding yeast, which is orthologous to AMPK-activated protein kinase (AMPK) in higher organisms. As its name suggests, mammalian AMPK is regulated by changes in the ratio of AMP to ATP, a sensitive indicator of the energy state of the cell. Now, three papers report the intriguing observation that an alternative pathway mediated by a Ca2+-dependent protein kinase is also capable of regulating AMPK (Hawley et al., 2005, Hurley et al., 2005 and Woods et al., 2005).