Volume 17 Issue 12, December 2010

Heat shock protein 90 (Hsp90) was the focus of a recent meeting in the Swiss Alps, where the Hsp90 community met to discuss the operation and functions of this ubiquitous and essential molecular chaperone.

Alterations in BRCA1 transcription can contribute to sporadic forms of breast cancer. Now the dynamics between transcriptional coactivators and co-repressors at the BRCA1 promoter reveal a central role for the metabolic sensor CtBP in the response to estrogen or cellular metabolic status

Circadian rhythms rely on a molecular clock that effects specific gene expression. Recently it has become clear that there is a tight connection between circadian gene transcription and histone acetylation. Histone methyltransferase MLL1, and its product histone H3K4me3, are now shown to cycle at clock-responsive promoters. The former binds key circadian transcription factors and is required for rhythmic gene expression and chromatin modification.

Amyloid fibrils feature in many human diseases and in epigenetic memory, but understanding their molecular structure has been difficult. Now, through a combination of optical trapping and fluorescent imaging to examine amyloid fibrils of the yeast prion protein Sup35, the unexpected unfolding of individual subdomains has been detected, suggesting strong noncovalent interactions maintain the fibril even if individual monomers unfold.

A high-resolution structure of an off-pathway misfolded intermediate state of a PDZ domain is now obtained, through a combination of phi-value analysis and computational modeling. The structure reveals that a misfolded intermediate can look quite similar to the native state.

In yeast cells, short telomeres are preferentially elongated by the telomerase complex in a process that requires Tel1. Now low levels of telomerase inhibitory protein Rif2 and the absence of Mec1 are shown to mark short telomeres for Tel1 binding and elongation rather than double-strand break repair.

Dom34 and Hbs1 are involved in no-go decay (NGD) and nonfunctional 18S rRNA decay (18S NRD) pathways that eliminate RNAs causing translation stalling. Now structural work reveals the similarity of the Dom34–Hbs1 complex with elongation factor–tRNA and translation termination eRF1–eRF3 complexes. Mutagenesis analysis of Hbs1 shows that NGD and 18S NRD can be genetically uncoupled.

Reverse transcriptase is an essential enzyme for HIV replication. Single-molecule studies reveal for the first time the structural dynamics of the reverse transcription initiation complex in real time. Reverse transcriptase can bind its tRNA–vRNA substrate in two opposite orientations and flip between these two states.

Mutations in BRCA2 are associated with higher susceptibility to some forms of cancer. BRCA2 is known to play a central role in the repair of DNA breaks via homologous recombination. Now a role for BRCA2 in telomere integrity is revealed, indicating that BRCA2 can contribute to genome stability in multiple ways.

tRNA and mRNA translocation on the ribosome is catalyzed by the GTPase EF-G. Using single-molecule FRET analysis, this process is examined, indicating that GTP hydrolysis does not affect translation through promoting a ribosomal unlocked state, but that constraining the conformation of EF-G to a high-affinity interaction with the ribosome is key to translocation rate.

Resection of DNA double strands is known to require a number of factors, but the exact roles each one plays in the process are still unclear. Now the resection events in yeast are reconstituted biochemically, showing that the MRX complex and Sae2 directly stimulate the resection of 5' strands by Exo1.

A number of antibodies against the membrane-proximal region of HIV-1 gp41 cannot neutralize the virus, despite their high affinity. Now binding studies along with a crystal structure indicate that these non-neutralizing antibodies recognize gp41 in a post-fusion conformation.

Despite recognizing an epitope on HIV-1 gp41 that partially overlaps with those from broadly neutralizing antibodies, mAb 13H11 is non-neutralizing. Now the crystal structure and binding studies of 13H11 Fab with a gp41 peptide reveal why: the antigen assumes a helical structure consistent with the post-fusion conformation of gp41.

Chromatin carries various modifications that have been related to DNA and RNA metabolism. Analysis of numerous histone modifications across the human genome now demonstrates that intronic and exonic regions are enriched with distinct modifications. Studies of two alternatively spliced genes suggest that exon definition, rather than splicing, may contribute to these patterns.

Nucleosomes consist of two copies of each histone. H2A.Z is a variant H2A-related histone known to be enriched around transcription start sites. However, an H2A.Z-containing nucleosome could contain contain two copies of H2A.Z (homotypic) or one of H2A.Z and one of canonical H2A (heterotypic). Homotypic and heterotypic H2A.Z nucleosomes are now mapped and their distributions relative to promoters analyzed.