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- Characterization of a DNA exit gate in the human cohesin ring. [Journal Article, Research Support, Non-U.S. Gov't]
- Science 2014 Nov 21; 346(6212):968-72.
Chromosome segregation depends on sister chromatid cohesion mediated by cohesin. The cohesin subunits Smc1, Smc3, and Scc1 form tripartite rings that are thought to open at distinct sites to allow entry and exit of DNA. However, direct evidence for the existence of open forms of cohesin is lacking. We found that cohesin's proposed DNA exit gate is formed by interactions between Scc1 and the coiled-coil region of Smc3. Mutation of this interface abolished cohesin's ability to stably associate with chromatin and to mediate cohesion. Electron microscopy revealed that weakening of the Smc3-Scc1 interface resulted in opening of cohesin rings, as did proteolytic cleavage of Scc1. These open forms may resemble intermediate states of cohesin normally generated by the release factor Wapl and the protease separase, respectively.
- Closing the cohesin ring: structure and function of its Smc3-kleisin interface. [Journal Article, Research Support, Non-U.S. Gov't]
- Science 2014 Nov 21; 346(6212):963-7.
Through their association with a kleisin subunit (Scc1), cohesin's Smc1 and Smc3 subunits are thought to form tripartite rings that mediate sister chromatid cohesion. Unlike the structure of Smc1/Smc3 and Smc1/Scc1 interfaces, that of Smc3/Scc1 is not known. Disconnection of this interface is thought to release cohesin from chromosomes in a process regulated by acetylation. We show here that the N-terminal domain of yeast Scc1 contains two α helices, forming a four-helix bundle with the coiled coil emerging from Smc3's adenosine triphosphatase head. Mutations affecting this interaction compromise cohesin's association with chromosomes. The interface is far from Smc3 residues, whose acetylation prevents cohesin's dissociation from chromosomes. Cohesin complexes holding chromatids together in vivo do indeed have the configuration of hetero-trimeric rings, and sister DNAs are entrapped within these.
- Dialogue between skin microbiota and immunity. [Journal Article, Research Support, N.I.H., Intramural]
- Science 2014 Nov 21; 346(6212):954-9.
Human skin, the body's largest organ, functions as a physical barrier to bar the entry of foreign pathogens, while concomitantly providing a home to myriad commensals. Over a human's life span, keratinized skin cells, immune cells, and microbes all interact to integrate the processes of maintaining skin's physical and immune barrier under homeostatic healthy conditions and also under multiple stresses, such as wounding or infection. In this Review, we explore the intricate interactions of microbes and immune cells on the skin surface and within associated appendages to regulate this orchestrated maturation in the context of both host physiological changes and environmental challenges.
- The gentle touch receptors of mammalian skin. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
- Science 2014 Nov 21; 346(6212):950-4.
The skin is our largest sensory organ, transmitting pain, temperature, itch, and touch information to the central nervous system. Touch sensations are conveyed by distinct combinations of mechanosensory end organs and the low-threshold mechanoreceptors (LTMRs) that innervate them. Here we explore the various structures underlying the diverse functions of cutaneous LTMR end organs. Beyond anchoring of LTMRs to the surrounding dermis and epidermis, recent evidence suggests that the non-neuronal components of end organs play an active role in signaling to LTMRs and may physically gate force-sensitive channels in these receptors. Combined with LTMR intrinsic properties, the balance of these factors comprises the response properties of mechanosensory neurons and, thus, the neural encoding of touch.
- The melanoma revolution: from UV carcinogenesis to a new era in therapeutics. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.]
- Science 2014 Nov 21; 346(6212):945-9.
Melanoma, the deadliest form of skin cancer, is an aggressive disease that is rising in incidence. Although melanoma is a historically treatment-resistant malignancy, in recent years unprecedented breakthroughs in targeted therapies and immunotherapies have revolutionized the standard of care for patients with advanced disease. Here, we provide an overview of recent developments in our understanding of melanoma risk factors, genomics, and molecular pathogenesis and how these insights have driven advances in melanoma treatment. In addition, we review benefits and limitations of current therapies and look ahead to continued progress in melanoma prevention and therapy. Remarkable achievements in the field have already produced a paradigm shift in melanoma treatment: Metastatic melanoma, once considered incurable, can now be treated with potentially curative rather than palliative intent.
- Advances in skin grafting and treatment of cutaneous wounds. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.]
- Science 2014 Nov 21; 346(6212):941-5.
The ability of the skin to repair itself after injury is vital to human survival and is disrupted in a spectrum of disorders. The process of cutaneous wound healing is complex, requiring a coordinated response by immune cells, hematopoietic cells, and resident cells of the skin. We review the classic paradigms of wound healing and evaluate how recent discoveries have enriched our understanding of this process. We evaluate current and experimental approaches to treating cutaneous wounds, with an emphasis on cell-based therapies and skin transplantation.
- Mammalian skin cell biology: at the interface between laboratory and clinic. [Journal Article, Research Support, Non-U.S. Gov't]
- Science 2014 Nov 21; 346(6212):937-40.
Mammalian skin research represents the convergence of three complementary disciplines: cell biology, mouse genetics, and dermatology. The skin provides a paradigm for current research in cell adhesion, inflammation, and tissue stem cells. Here, I discuss recent insights into the cell biology of skin. Single-cell analysis has revealed that human epidermal stem cells are heterogeneous and differentiate in response to multiple extrinsic signals. Live-cell imaging, optogenetics, and cell ablation experiments show skin cells to be remarkably dynamic. High-throughput, genome-wide approaches have yielded unprecedented insights into the circuitry that controls epidermal stem cell fate. Last, integrative biological analysis of human skin disorders has revealed unexpected functions for elements of the skin that were previously considered purely structural.
- Shedding light on skin color. [News]
- Science 2014 Nov 21; 346(6212):934-6.
- Skin. From bench to bedside. Introduction. [Introductory Journal Article]
- Science 2014 Nov 21; 346(6212):932-3.
- Older scientists get their due. [Comment, Letter]
- Science 2014 Nov 21; 346(6212):929.