Complete genome DNA sequence and analysis is presented for Wolbachia, the obligate alpha-proteobacterial endosymbiont required for fertility and survival of the human filarial parasitic nematode Brugia malayi. Although, quantitatively, the genome is even more degraded than those of closely related Rickettsia species, Wolbachia has retained more intact metabolic pathways. The ability to provide riboflavin, flavin adenine dinucleotide, heme, and nucleotides is likely to be Wolbachia's principal contribution to the mutualistic relationship, whereas the host nematode likely supplies amino acids required for Wolbachia growth. Genome comparison of the Wolbachia endosymbiont of B. malayi (wBm) with the Wolbachia endosymbiont of Drosophila melanogaster (wMel) shows that they share similar metabolic trends, although their genomes show a high degree of genome shuffling. In contrast to wMel, wBm contains no prophage and has a reduced level of repeated DNA. Both Wolbachia have lost a considerable number of membrane biogenesis genes that apparently make them unable to synthesize lipid A, the usual component of proteobacterial membranes. However, differences in their peptidoglycan structures may reflect the mutualistic lifestyle of wBm in contrast to the parasitic lifestyle of wMel. The smaller genome size of wBm, relative to wMel, may reflect the loss of genes required for infecting host cells and avoiding host defense systems. Analysis of this first sequenced endosymbiont genome from a filarial nematode provides insight into endosymbiont evolution and additionally provides new potential targets for elimination of cutaneous and lymphatic human filarial disease.

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Germ line mutations in BRCA1 or BRCA2 genes result in a marked increase in the risk of early onset breast and ovarian cancers (5-10). BRCA1 and BRCA2 appear to have multiple functions including roles in transcriptional regulation (11)(12)(13)(14) and cell cycle checkpoint control (15)(16)(17)(18)(19)(20).1 Brca1 and Brca2 both have transcription activation functions (11, 13); Brca1 co-activates transcription with p53 (21,22). Recently it has been demonstrated that Brca1 participates in homologous recombinational repair pathways (2, 3). These observations are consistent with earlier work that demonstrated interaction of Brca1 and Brca2 with the recombinational repair protein Rad51, in addition to studies showing that brca1 and brca2 mutants are phenotypically similar to rad51 mutants (1,4,(23)(24)(25)(26).In addition to contributing to recombinational repair of double strand breaks (DSBs), 2 BRCA1 has also been implicated in other DNA repair pathways. Mutational analysis has shown a role for BRCA1 in transcription-coupled base excision repair of oxidative DNA damage (27,28). Furthermore, a recent study reported biochemical interactions between Brca1 and proteins required for DNA-end joining, nucleotide mismatch repair, DNA replication, and signal transduction in response to damage (29). This study also identified interactions between Brca1 and other proteins thought to be involved in recombinational repair. Although these results raise the possibility that BRCA1 contributes to multiple cellular DNA damage responses, the specific mechanisms through which BRCA1 contributes to these processes remain to be determined.Studies primarily in yeast have indicated that Rad51 promotes homology-dependent repair of DNA DSBs. The strand exchange activity of Rad51 catalyzes the exchange of genetic information between a damaged DNA molecule and an undamaged template copy (30,31). Similarly, studies have shown that the human Rad51 possesses DNA strand-exchange activity (32). Immunostaining analysis of yeast and mammalian cells undergoing DNA repair and recombination have revealed the presence of visible subnuclear assemblies of Rad51 (33,34). The properties of Rad51 foci indicate that they are multimeric nucleoprotein complexes engaged in recombinational repair (33-38). In mammalian cells, rad51 "knock-out" mice have been shown to display embryonic lethality and sensitivity to ionizing radiation indicating a role in mediating genome stability (26).Rad51 plays a central role in mediating homologous recombination events and can promote strand-exchange alone in vitro. However, its strand-exchange activity requires various accessory factors. For example, one category of accessory factor promotes assembly of Rad51 into the helical protein-DNA filaments needed for strand exchange. In yeast, biochemical (39 -42) and cytological (36) observations indicate that RPA, Rad55, Rad57, and Rad52 proteins promote the assembly of Rad51 during yeast meiotic recombination. Thus, one model for Rad51 assembly at sites of damage is that formation of t...

Brucella melitensis is a facultative intracellular bacterial pathogen that causes abortion in goats and sheep and Malta fever in humans. The genome of B. melitensis strain 16M was sequenced and found to contain 3,294,935 bp distributed over two circular chromosomes of 2,117,144 bp and 1,177,787 bp encoding 3,197 ORFs. By using the bioinformatics suite ERGO, 2,487 (78%) ORFs were assigned functions. The origins of replication of the two chromosomes are similar to those of other ␣-proteobacteria. Housekeeping genes, including those involved in DNA replication, transcription, translation, core metabolism, and cell wall biosynthesis, are distributed on both chromosomes. Type I, II, and III secretion systems are absent, but genes encoding sec-dependent, sec-independent, and flagellaspecific type III, type IV, and type V secretion systems as well as adhesins, invasins, and hemolysins were identified. Several features of the B. melitensis genome are similar to those of the symbiotic Sinorhizobium meliloti.

We present a complete DNA sequence and metabolic analysis of the dominant oral bacterium Fusobacterium nucleatum. Although not considered a major dental pathogen on its own, this anaerobe facilitates the aggregation and establishment of several other species including the dental pathogens Porphyromonas gingivalis and Bacteroides forsythus. The F. nucleatum strain ATCC 25586 genome was assembled from shotgun sequences and analyzed using the ERGO bioinformatics suite (http://www.integratedgenomics.com). The genome contains 2.17 Mb encoding 2,067 open reading frames, organized on a single circular chromosome with 27% GC content. Despite its taxonomic position among the gram-negative bacteria, several features of its core metabolism are similar to that of gram-positive Clostridium spp., Enterococcus spp., and Lactococcus spp. The genome analysis has revealed several key aspects of the pathways of organic acid, amino acid, carbohydrate, and lipid metabolism. Nine very-high-molecular-weight outer membrane proteins are predicted from the sequence, none of which has been reported in the literature. More than 137 transporters for the uptake of a variety of substrates such as peptides, sugars, metal ions, and cofactors have been identified. Biosynthetic pathways exist for only three amino acids: glutamate, aspartate, and asparagine. The remaining amino acids are imported as such or as di-or oligopeptides that are subsequently degraded in the cytoplasm. A principal source of energy appears to be the fermentation of glutamate to butyrate. Additionally, desulfuration of cysteine and methionine yields ammonia, H 2 S, methyl mercaptan, and butyrate, which are capable of arresting fibroblast growth, thus preventing wound healing and aiding penetration of the gingival epithelium. The metabolic capabilities of F. nucleatum revealed by its genome are therefore consistent with its specialized niche in the mouth.