Contact between sister chromatids from S phase to anaphase depends on cohesin, a large multi-subunit protein complex. Mutations in sister chromatid cohesion proteins underlie the human developmental condition, Cornelia de Lange Syndrome. Roles for cohesin in regulating gene expression, sometimes in combination with CCCTC-binding factor (CTCF), have emerged. We analyzed zebrafish embryos null for cohesin subunit rad21 using microarrays to determine global effects of cohesin on gene expression during embryogenesis. This identified Rad21-associated gene networks that included myca (zebrafish c-myc), p53 and mdm2. In zebrafish, cohesin binds to the transcription start sites of p53 and mdm2, and depletion of either Rad21 or CTCF increased their transcription. In contrast, myca expression was strongly downregulated upon loss of Rad21 while depletion of CTCF had little effect. Depletion of Rad21 or the cohesin-loading factor Nipped-B in Drosophila cells also reduced expression of myc and Myc target genes. Cohesin bound the transcription start site plus an upstream predicted CTCF binding site at zebrafish myca. Binding and positive regulation of the c-Myc gene by cohesin is conserved through evolution, indicating this regulation is likely to be direct. The exact mechanism of regulation is unknown, but local changes in histone modification associated with transcription repression at the myca gene were observed in rad21 mutants.

No abstract

Cohesin is a multisubunit protein complex that plays an integral role in sister chromatid cohesion, DNA repair, and meiosis. Of significance, both over-and underexpression of cohesin are associated with cancer. It is generally believed that cohesin dysregulation contributes to cancer by leading to aneuploidy or chromosome instability. For cancers with loss of cohesin function, this idea seems plausible. However, overexpression of cohesin in cancer appears to be more significant for prognosis than its loss. Increased levels of cohesin subunits correlate with poor prognosis and resistance to drug, hormone, and radiation therapies. However, if there is sufficient cohesin for sister chromatid cohesion, overexpression of cohesin subunits should not obligatorily lead to aneuploidy. This raises the possibility that excess cohesin promotes cancer by alternative mechanisms. Over the last decade, it has emerged that cohesin regulates gene transcription. Recent studies have shown that gene regulation by cohesin contributes to stem cell pluripotency and cell differentiation. Of importance, cohesin positively regulates the transcription of genes known to be dysregulated in cancer, such as Runx1, Runx3, and Myc. Furthermore, cohesin binds with estrogen receptor a throughout the genome in breast cancer cells, suggesting that it may be involved in the transcription of estrogen-responsive genes. Here, we will review evidence supporting the idea that the gene regulation function of cohesin represents a previously unrecognized mechanism for the development of cancer. Mol Cancer Res; 9(12);

No abstract

No abstract