No abstract

Cohesion factors pair together sister chromatids from early S-phase until anaphase onset. Numerous findings also establish an additional role in transcription. In humans, mutations in cohesion factors result in developmental abnormalities such as Cornelia de Lange, Roberts Syndrome/SC-Phocomelia, Rothman-Thompson Syndrome and others. While clinically relevant, a detailed study that links experimentally-defined cohesin defects to transcriptional changes remains lacking. Here, we report on the effects of cohesin inactivation during an early and discrete portion of the cell cycle. Even transient cohesin inactivation in α-factor arrested cells to target the G1 portion of the cell cycle results in significant and reproducible changes in transcription. Surprisingly, over a third of the affected genes exhibit inter-related functions, suggesting that cohesin positioning along chromosomes evolved to coordinate gene expression. Prior studies indicate that defects in rRNA maturation/ribosome biogenesis produce developmental maladies in humans. Thus, the identification of genes critical for rRNA maturation in this study is of particular interest.

No abstract

Mutations in BRCA1 account for a significant proportion of hereditary breast and ovarian cancers, but analysis of BRCA1 function is complicated by pleiotropic effects and binding partners (Pol II holoenzyme and transcription factors, chromatin remodelers, recombination complexes and E3 ligases). In vertebrate cells, efforts to elucidate BRCA1 transcriptional effects have focused on specific genes or restricted portions of the genome—limiting analyses of BRCA1 effects on adjoining DNA sequences and along chromosome lengths. Here, we use microarray analyses on the genetically tractable yeast cell system to elucidate BRCA1-dependent genome-wide positional effects on both gene induction and repression. Yeast responses may be of clinical relevance based on findings that BRCA1 severely diminishes yeast growth kinetics but that BRCA1 mutated at sites identified from breast tumors is no longer able to retard yeast cell growth kinetics. Our analysis suggests that BRCA1 acts through both transcription factors to upregulate specific loci and chromatin remodeling complexes to effect global changes in gene expression. BRCA1 also exhibits gene repression activities. Cluster-functional analysis reveals that these repressed factors are required for mitotic stability and provide a novel molecular explanation for the conditional lethality observed between BRCA1 and chromosome segregation genes.