Loop extrusion by structural maintenance of chromosomes (SMC) complexes has been proposed as a mechanism to organize chromatin in interphase and metaphase. However, the requirements for chromatin organization in these cell cycle phases are different, and it is unknown whether loop extrusion dynamics and the complexes that extrude DNA also differ. Here, we used Xenopus egg extracts to reconstitute and image loop extrusion of single DNA molecules during the cell cycle. We show that loops form in both metaphase and interphase, but with distinct dynamic properties. Condensin extrudes DNA loops non-symmetrically in metaphase, whereas cohesin extrudes loops symmetrically in interphase. Our data show that loop extrusion is a general mechanism underlying DNA organization, with dynamic and structural properties that are biochemically regulated during the cell cycle.

Vitamin D signaling regulates cell proliferation and differentiation, and epidemiological data suggest that it functions as a cancer chemopreventive agent, although the underlying mechanisms are poorly understood. Vitamin D signaling can suppress expression of genes regulated by c-MYC, a transcription factor that controls epidermal differentiation and cell proliferation and whose activity is frequently elevated in cancer. We show through cell-and animal-based studies and mathematical modeling that hormonal 1,25-dihydroxyvitamin D (1,25D) and the vitamin D receptor (VDR) profoundly alter, through multiple mechanisms, the balance in function of c-MYC and its antagonist the transcriptional repressor MAD1/MXD1. 1,25D inhibited transcription of c-MYC-regulated genes in vitro, and topical 1,25D suppressed expression of c-MYC and its target setd8 in mouse skin, whereas MXD1 levels increased. 1,25D inhibited MYC gene expression and accelerated its protein turnover. In contrast, it enhanced MXD1 expression and stability, dramatically altering ratios of DNA-bound c-MYC and MXD1. Remarkably, F-box protein FBW7, an E3-ubiquitin ligase, controlled stability of both arms of the c-MYC/MXD1 push-pull network, and FBW7 ablation attenuated 1,25D regulation of c-MYC and MXD1 turnover. Additionally, c-MYC expression increased upon VDR knockdown, an effect abrogated by ablation of MYC regulator β-catenin. c-MYC levels were widely elevated in vdr −/− mice, including in intestinal epithelium, where hyperproliferation has been reported, and in skin epithelia, where phenotypes of VDR-deficient mice and those overexpressing epidermal c-MYC are similar. Thus, 1,25D and the VDR regulate the c-MYC/MXD1 network to suppress c-MYC function, providing a molecular basis for cancer preventive actions of vitamin D.V itamin D is obtained naturally from limited dietary sources. It is also generated by cutaneous conversion of 7-dehydrocholesterol in the presence of adequate surface solar UV-B radiation, which varies with latitude and time of year (1). Vitamin D has attracted broad clinical interest because insufficiency or deficiency is widespread in several populations worldwide (2-4). Although initially identified as a regulator of calcium homeostasis, vitamin D is now known to have a broad spectrum of actions, driven by the virtually ubiquitous expression of the vitamin D receptor (VDR), a nuclear receptor and hormone-regulated transcription factor. For example, it acts as a chemopreventive agent in several animal models of cancer and induces cell-cycle arrest and nonmalignant and malignant cell differentiation (5-11). Epidemiological data have provided associations between lack of UV-B exposure, vitamin D insufficiency, and the prevalence of certain cancers (12). A large prospective study associated vitamin D sufficiency with reduced total cancer incidence and mortality, particularly in digestive cancers [head and neck squamous cell carcinoma (HNSCC), esophageal, pancreatic, stomach, and colorectal cancers] and leukemias (13). VDR gene polymorphi...