Table of contents



Keeping up with the times p1399


As the season changes, daylight shifts and a new year looms, we consider cycles and the intrinsic clock that drives us.


Meeting Report

Understanding of the Hsp90 molecular chaperone reaches new heights pp1400 - 1404

Cara K Vaughan, Len Neckers & Peter W Piper


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.


Research Highlights

Research highlights p1405




Transcriptional regulation of BRCA1 expression by a metabolic switch pp1406 - 1413

Li-Jun Di, Alfonso G Fernandez, Adriana De Siervi, Dan L Longo & Kevin Gardner


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

The histone methyltransferase MLL1 permits the oscillation of circadian gene expression pp1414 - 1421

Sayako Katada & Paolo Sassone-Corsi


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.

Optical trapping with high forces reveals unexpected behaviors of prion fibrils pp1422 - 1430

Jijun Dong, Carlos E Castro, Mary C Boyce, Matthew J Lang & Susan Lindquist


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.

Structural characterization of a misfolded intermediate populated during the folding process of a PDZ domain pp1431 - 1437

Stefano Gianni, Ylva Ivarsson, Alfonso De Simone, Carlo Travaglini-Allocatelli, Maurizio Brunori & Michele Vendruscolo


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.

Reduced Rif2 and lack of Mec1 target short telomeres for elongation rather than double-strand break repair pp1438 - 1445

Jean S McGee, Jane A Phillips, Angela Chan, Michelle Sabourin, Katrin Paeschke & Virginia A Zakian


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.

Dissection of Dom34–Hbs1 reveals independent functions in two RNA quality control pathways pp1446 - 1452

Antonia M G van den Elzen, Julien Henri, Noureddine Lazar, María Eugenia Gas, Dominique Durand, François Lacroute, Magali Nicaise, Herman van Tilbeurgh, Bertrand Séraphin & Marc Graille


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.

Initiation complex dynamics direct the transitions between distinct phases of early HIV reverse transcription pp1453 - 1460

Shixin Liu, Bryan T Harada, Jennifer T Miller, Stuart F J Le Grice & Xiaowei Zhuang


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.

BRCA2 acts as a RAD51 loader to facilitate telomere replication and capping pp1461 - 1469

Sophie Badie, Jose M Escandell, Peter Bouwman, Ana Rita Carlos, Maria Thanasoula, Maria M Gallardo, Anitha Suram, Isabel Jaco, Javier Benitez, Utz Herbig, Maria A Blasco, Jos Jonkers & Madalena Tarsounas


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.

Correlated conformational events in EF-G and the ribosome regulate translocation pp1470 - 1477

James B Munro, Michael R Wasserman, Roger B Altman, Leyi Wang & Scott C Blanchard


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.

Mre11–Rad50–Xrs2 and Sae2 promote 5′ strand resection of DNA double-strand breaks pp1478 - 1485

Matthew L Nicolette, Kihoon Lee, Zhi Guo, Mridula Rani, Julia M Chow, Sang Eun Lee & Tanya T Paull


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.

Distinct conformational states of HIV-1 gp41 are recognized by neutralizing and non-neutralizing antibodies pp1486 - 1491

Gary Frey, Jia Chen, Sophia Rits-Volloch, Michael M Freeman, Susan Zolla-Pazner & Bing Chen


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.


Brief Communication

Crystal structure of a non-neutralizing antibody to the HIV-1 gp41 membrane-proximal external region pp1492 - 1494

Nathan I Nicely, S Moses Dennison, Leonard Spicer, Richard M Scearce, Garnett Kelsoe, Yoshihiro Ueda, Haiyan Chen, Hua-Xin Liao, S Munir Alam & Barton F Haynes


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.



Reciprocal intronic and exonic histone modification regions in humans pp1495 - 1499

Jason T Huff, Alex M Plocik, Christine Guthrie & Keith R Yamamoto


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.



H2A.Z nucleosomes enriched over active genes are homotypic pp1500 - 1507

Christopher M Weber, Jorja G Henikoff & Steven Henikoff


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.