Activation-induced cytidine deaminase turns on somatic hypermutation in hybridomas

The production of high-affinity protective antibodies requires somatic hypermutation (SHM) of the antibody variable (V)-region genes. SHM is characterized by a high frequency of point mutations that occur only during the centroblast stage of B-cell differentiation. Activation-induced cytidine deaminase (AID), which is expressed specifically in germinal-centre centroblasts, is required for this process, but its exact role is unknown. Here we show that AID is required for SHM in the centroblast-like Ramos cells, and that expression of AID is sufficient to induce SHM in hybridoma cells, which represent a later stage of B-cell differentiation that does not normally undergo SHM. In one hybridoma, mutations were exclusively in G*C base pairs that were mostly within RGYW or WRCY motifs, suggesting that AID has primary responsibility for mutations at these nucleotides. The activation of SHM in hybridomas indicates that AID does not require other centroblast-specific cofactors to induce SHM, suggesting either that it functions alone or that the factors it requires are expressed at other stages of B-cell differentiation.     

Portrait of a molecule

The double helix is idealized for its aesthetic elegant structure, but the reality of DNA's physical existence is quite different. Most DNA in the cell is compressed into a tangled package that somehow still exposes itself to meticulous gene-regulatory control. Philip Ball holds a mirror up to what we truly know about the mysteries of DNA's life inside a cell.     

Spatial proximity of translocation-prone gene loci in human lymphomas

Cancer cells frequently have disease-specific chromosome rearrangements. It is poorly understood why translocations between chromosomes recur at specific breakpoints in the genome. Here we provide evidence that higher-order spatial genome organization is a contributing factor in the formation of recurrent translocations. We show that MYC, BCL and immunoglobulin loci, which are recurrently translocated in various B-cell lymphomas, are preferentially positioned in close spatial proximity relative to each other in normal B cells. Loci in spatial proximity are non-randomly positioned towards the nuclear interior in normal B cells. This locus proximity is the consequence of higher-order genome structure rather than a property of individual genes. Our results suggest that the formation of specific translocations in human lymphomas, and perhaps other tissues, is determined in part by higher-order spatial organization of the genome.     

A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis

Smith-Lemli-Opitz syndrome (SLOS), desmosterolosis and lathosterolosis are human syndromes caused by defects in the final stages of cholesterol biosynthesis. Many of the developmental malformations in these syndromes occur in tissues and structures whose embryonic patterning depends on signaling by the Hedgehog (Hh) family of secreted proteins. Here we report that response to the Hh signal is compromised in mutant cells from mouse models of SLOS and lathosterolosis and in normal cells pharmacologically depleted of sterols. We show that decreasing levels of cellular sterols correlate with diminishing responsiveness to the Hh signal. This diminished response occurs at sterol levels sufficient for normal autoprocessing of Hh protein, which requires cholesterol as cofactor and covalent adduct. We further find that sterol depletion affects the activity of Smoothened (Smo), an essential component of the Hh signal transduction apparatus.     

从服务中心到战略推动者:香港中文大学信息化建设的未来展望

香港中文大学历经半个世纪风雨,如今已发展成为世界知名研究型大学.与此同时,计算机和网络技术的日新月异,极大地改变着人们的生活、学习、工作和社交模式,也给大学提出了源源不断的新挑战.如今,IT已不再是实验室里高高在上的尖端科技,而是维持社会正常运作的基础设施和服务,并且拥有着巨大的潜力给生活带来更多的智慧.作为高等教育的IT部门,如何应对这业务格局的转变,如何了解和满足用户日益提升的服务需求,如何发挥IT技术的价值以推动大学战略发展,都是我们应当考虑的问题.本文将介绍香港中文大学的信息化管理与发展现状,讨论当前遇到的问题并分析应对方法,探索为实现大学信息化战略推动者之愿景应选择的未来道路.