Recent sequencing and assembly of the genome for the fungal pathogen Candida albicans used simple automated procedures for the identification of putative genes. We have reviewed the entire assembly, both by hand and with additional bioinformatic resources, to accurately map and describe 6,354 genes and to identify 246 genes whose original database entries contained sequencing errors (or possibly mutations) that affect their reading frame. Comparison with other fungal genomes permitted the identification of numerous fungus-specific genes that might be targeted for antifungal therapy. We also observed that, compared to other fungi, the protein-coding sequences in the C. albicans genome are especially rich in short sequence repeats. Finally, our improved annotation permitted a detailed analysis of several multigene families, and comparative genomic studies showed that C. albicans has a far greater catabolic range, encoding respiratory Complex 1, several novel oxidoreductases and ketone body degrading enzymes, malonyl-CoA and enoyl-CoA carriers, several novel amino acid degrading enzymes, a variety of secreted catabolic lipases and proteases, and numerous transporters to assimilate the resulting nutrients. The results of these efforts will ensure that the Candida research community has uniform and comprehensive genomic information for medical research as well as for future diagnostic and therapeutic applications.

Molecular classification of cancers into subtypes has resulted in an advance in our understanding of tumour biology and treatment response across multiple tumour types. However, to date, cancer profiling has largely focused on protein-coding genes, which comprise <1% of the genome. Here we leverage a compendium of 58,648 long noncoding RNAs (lncRNAs) to subtype 947 breast cancer samples. We show that lncRNA-based profiling categorizes breast tumours by their known molecular subtypes in breast cancer. We identify a cohort of breast cancer-associated and oestrogen-regulated lncRNAs, and investigate the role of the top prioritized oestrogen receptor (ER)-regulated lncRNA, DSCAM-AS1. We demonstrate that DSCAM-AS1 mediates tumour progression and tamoxifen resistance and identify hnRNPL as an interacting protein involved in the mechanism of DSCAM-AS1 action. By highlighting the role of DSCAM-AS1 in breast cancer biology and treatment resistance, this study provides insight into the potential clinical implications of lncRNAs in breast cancer.

Candida albicans, the most prevalent fungal pathogen of humans, has recently been shown to undergo mating. Here we describe a mating pheromone produced by C. albicans ␣ cells and show that the gene which encodes it (MF␣) is required for ␣ cells, but not a cells, to mate. We also identify the receptor for this mating pheromone as the product of the STE2 gene and show that this gene is required for the mating of a cells, but not ␣ cells. Cells of the a mating type respond to the ␣ mating pheromone by producing long polarized projections, similar to those observed in bona fide mating mixtures of C. albicans a and ␣ cells. During this process, transcription of approximately 62 genes is induced. Although some of these genes correspond to those induced in Saccharomyces cerevisiae by S. cerevisiae ␣-factor, most are specific to the C. albicans pheromone response. The most surprising class encode cell surface and secreted proteins previously implicated in virulence of C. albicans in a mouse model of disseminated candidiasis. This observation suggests that aspects of cell-cell communication in mating may have been evolutionarily adopted for host-pathogen interactions in C. albicans.Candida albicans is the most common fungal pathogen in humans and is responsible for a wide variety of mucosal and systemic infections (9). Two aspects of C. albicans biology are examined in this paper. The first is a group of hypha-specific gene products required for full virulence in a disseminated model of candidiasis. These genes include HWP1 (whose product is required for efficient attachment to epithelial cells) (38), SAP4, SAP5, and SAP6 (which encode aspartyl proteases required for tissue invasion) (6, 12), RBT1 and ECE1 (which encode cell surface proteins of unknown function), and RBT4

BvgS and BvgA, a two‐component system, regulate virulence gene expression in Bordetella pertussis. BvgS is a transmembrane sensor protein that can autophosphorylate and phosphorylate BvgA. Phosphorylated BvgA activates transcription of virulence genes. The cytoplasmic region of BvgS contains three domains separated by alanine/proline‐rich sequences–the transmitter, receiver and C‐terminus. We report that the C‐terminal domain, like the transmitter and receiver, is an essential part of the phosphorelay from BvgS to BvgA. The BvgS C‐terminal domain is phosphorylated in trans via a phosphotransfer mechanism by the cytoplasmic portion of BvgS, and trans‐phosphorylation of the C‐terminal domain requires both the transmitter and receiver. We also demonstrate that phosphorylated, purified C‐terminal domain alone is sufficient for phosphotransfer to BvgA. A point mutation in the C‐terminal domain (His1172–>Gln) abolishes BvgS activity in vivo and eliminates detectable phosphorylation of BvgA in vitro. Activity of BvgS His 1172–>Gln could be restored by providing the wild‐type C‐terminal domain in trans. Our results indicate an obligatory role for an alternate phosphodonor module in the BvgAS phosphorelay.

Candida albicans is the most prevalent human fungal pathogen. Here, we take advantage of haploinsuf®-ciency and transposon mutagenesis to perform largescale loss-of-function genetic screen in this organism. We identi®ed mutations in 146 genes that affect the switch between its single-cell (yeast) form and ®lamen-tous forms of growth; this switch appears central to the virulence of C.albicans. The encoded proteins include those involved in nutrient sensing, signal transduction, transcriptional control, cytoskeletal organization and cell wall construction. Approximately one-third of the genes identi®ed in the screen lack homologs in Saccharomyces cerevisiae and other model organisms and thus constitute candidate antifungal drug targets. These results illustrate the value of performing forward genetic studies in bona ®de pathogens.

The RNA-binding protein RC3H1 (also known as ROQUIN) promotes TNFα mRNA decay via a 3′UTR constitutive decay element (CDE). Here we applied PAR-CLIP to human RC3H1 to identify ∼3,800 mRNA targets with >16,000 binding sites. A large number of sites are distinct from the consensus CDE and revealed a structure-sequence motif with U-rich sequences embedded in hairpins. RC3H1 binds preferentially short-lived and DNA damage-induced mRNAs, indicating a role of this RNA-binding protein in the post-transcriptional regulation of the DNA damage response. Intriguingly, RC3H1 affects expression of the NF-κB pathway regulators such as IκBα and A20. RC3H1 uses ROQ and Zn-finger domains to contact a binding site in the A20 3′UTR, demonstrating a not yet recognized mode of RC3H1 binding. Knockdown of RC3H1 resulted in increased A20 protein expression, thereby interfering with IκB kinase and NF-κB activities, demonstrating that RC3H1 can modulate the activity of the IKK/NF-κB pathway.

The androgen receptor (AR) plays a critical role in the development of the normal prostate as well as prostate cancer. Using an integrative transcriptomic analysis of prostate cancer cell lines and tissues, we identified ARLNC1 (AR-regulated long non-coding RNA 1) as an important long non-coding RNA that is strongly associated with AR signaling in prostate cancer progression. Not only was ARLNC1 induced by AR protein, ARLNC1 stabilized the AR transcript via RNA-RNA interaction. ARLNC1 knockdown suppressed AR expression, global AR signaling, and prostate cancer growth in vitro and in vivo. Taken together, these data support a role for ARLNC1 in maintaining a positive feedback loop that potentiates AR signaling during prostate cancer progression, and identifies ARLNC1 as a novel therapeutic target.

Expression of adhesins, toxins, and other virulence factors of Bordetella pertussis is under control of the BvgA and BvgS proteins, members of a bacterial twocomponent signal transduction family. BvgA bears sequence simlarity to regulator components, whereas BvgS shows similarity to both sensor and regulator components. BvgA and the cytoplasmic portion of BvgS ('BvgS) were overexpressed and purified. 'BvgS autophosphorylated with the vphosphate from