Hot off the presses! Apr 01 Trends Biochem Sci

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Latest Articles Include:

• Editorial Board
  - Trends Biochem Sci 34(4):i (2009)
  
• PUPylation: something old, something new, something borrowed, something Glu
  - Trends Biochem Sci 34(4):155-158 (2009)
  Most eukaryotic proteins are degraded by the 26S proteasome as a consequence of their covalent modification with ubiquitin. Although the proteasome is found in some prokaryotes, ubiquitin is not, which indicates that substrates are targeted to prokaryotic proteasomes by a fundamentally different mechanism. A recent study has identified Pup (prokaryotic ubiquitin-like protein) as a mycobacterial protein that functions in a manner analogous to ubiquitin for proteasome-dependent proteolysis in prokaryotes.
• H2A.Z and DNA methylation: irreconcilable differences
  - Trends Biochem Sci 34(4):158-161 (2009)
  DNA methylation state and the composition of the nucleosome core particle influence chromatin structure and, in turn, transcriptional competence. Although it is clear that chromatin remodeling and covalent histone modifications regulate DNA methylation in plants and animals, the role of histone variants in directing DNA methylation, and vice versa, has not been addressed. A new genome-wide study in Arabidopsis thaliana reveals a broadly antagonistic relationship between H2A.Z occupancy and DNA methylation.
• Pinning down HER2–ER crosstalk in SMRT regulation
  - Trends Biochem Sci 34(4):162-165 (2009)
  SMRT (silencing mediator for retinoic acid and thyroid hormone receptors) is a transcriptional co-repressor that mediates the repressive function of nuclear hormone receptors such as the estrogen receptor (ER). Decreased SMRT levels correlate with acquired tamoxifen resistance in breast cancer, and SMRT restoration might resensitize breast cancer cells to tamoxifen. A new study demonstrates that SMRT protein stability is regulated by phosphorylation-dependent Pin1-catalyzed prolyl-isomerization. Pin1 functions downstream of HER2, positioning it as an important modulator of the crosstalk between ER and growth factor signaling.
• On the origin of the cap-dependent initiation of translation in eukaryotes
  - Trends Biochem Sci 34(4):166-175 (2009)
  The Shine-Dalgarno sequence of prokaryotic mRNAs, which helps to bind and position the ribosome at the start site for protein synthesis, is absent from eukaryotic mRNAs. Instead, for most, a structure at the 5′ end and a much larger number of protein initiation factors are needed for both binding of the ribosome and for successful start-site selection, that is, a 'cap-dependent' initiation mechanism. Although the mechanics of this process are well studied, what is not clear is how it evolved. By analyzing recent progress in different fields, I suggest that it was the need to adjust to the arrival of the nuclear membrane and the subsequent requirement to export intron-less mRNAs to the cytoplasm that spurred the shift to the more complex translation initiation mechanism in eukaryotes.
• NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer
  - Trends Biochem Sci 34(4):176-188 (2009)
  Transcription factor nuclear factor-erythroid 2-related factor 2 (NRF2) controls cellular adaptation to oxidants and electrophiles by inducing antioxidant and detoxification genes in response to redox stress. NRF2 is negatively regulated by Kelch-like ECH-associated protein 1 (KEAP1). Tumours from not, vert, similar15% of patients with lung cancer harbour somatic mutations in KEAP1 that prevent effective NRF2 repression. Recently, two NRF2 mutation 'hot-spots' were identified in not, vert, similar10% of patients with lung cancer, enabling the transcription factor to evade KEAP1-mediated repression. Somatic mutations in KEAP1 and NRF2 provide an insight into the molecular mechanisms by which NRF2 is regulated. Moreover, constitutive NRF2 activation might cause drug resistance in tumours, and an understanding of how the transcription factor is regulated indicates ways in which this could be overcome.
• The ribozyme core of group II introns: a structure in want of partners
  - Trends Biochem Sci 34(4):189-199 (2009)
  Group II introns contain a large ribozyme, which catalyzes self-splicing, and the coding sequence of a reverse transcriptase, the function of which is to cooperate with the ribozyme to achieve genomic mobility. Despite its lack of substrates for both steps of the splicing process, the crystal structure of a group II ribozyme reveals the location of two metal ions most likely to be involved in catalysis; the RNA structure that binds to these ions results from the bending of a local motif by the folding of the rest of the ribozyme. The stage is now set to determine where the intron-encoded protein binds to its partner and whether the spliceosome uses a counterpart of the group II catalytic center to excise nuclear pre-messenger introns.
• Sumoylation and human disease pathogenesis
  - Trends Biochem Sci 34(4):200-205 (2009)
  Covalent modification by SUMO polypeptides, or sumoylation, is an important regulator of the functional properties of many proteins. Among these are several proteins implicated in human diseases including cancer, Huntington's, Alzheimer's, and Parkinson's diseases, as well as spinocerebellar ataxia 1 and amyotrophic lateral sclerosis. Recent reports reveal two new examples of human disease-associated proteins that are SUMO modified: amyloid precursor protein and lamin A. These findings point to a function for sumoylation in modulating amyloid-β peptide levels, indicating a potential role in Alzheimer's disease, and for decreased lamin A sumoylation as a causative factor in familial dilated cardiomyopathy.
• Co-evolution of primordial membranes and membrane proteins
  - Trends Biochem Sci 34(4):206-215 (2009)
  Studies of the past several decades have provided major insights into the structural organization of biological membranes and mechanisms of many membrane molecular machines. However, the origin(s) of the membrane(s) and membrane proteins remains enigmatic. We discuss different concepts of the origin and early evolution of membranes with a focus on the evolution of the (im)permeability to charged molecules such as proteins, nucleic acids and small ions. Reconstruction of the evolution of F-type and A/V-type membrane ATPases (ATP synthases), which are either proton- or sodium-dependent, might help us to understand not only the origin of membrane bioenergetics but also of membranes themselves. We argue that evolution of biological membranes occurred as a process of co-evolution of lipid bilayers, membrane proteins and membrane bioenergetics.