Medical Education From a Theory-Practice-Philosophy Perspective.

Medical schooling, at least as structured in the United States and Canada, is commonly assembled intuitively or empirically to meet concrete goals. Despite a long history of scholarship in educational theory to address how people learn, this is rarely examined during medical curriculum design. We provide a historical perspective on educational theory-practice-philosophy and a tool to aid faculty in learning how to identify and use theory-practice-philosophy for the design of curriculum and instruction.

A WW-like module in the RAG1 N-terminal domain contributes to previously unidentified protein-protein interactions.

More than one-third of the RAG1 protein can be truncated from the N-terminus with only subtle effects on the products of V(D)J recombination in vitro or in a mouse. What, then, is the function of the N-terminal domain? We believe it to be regulatory. We determined, several years ago, that an included RING motif could function as an ubiquitin E3 ligase.

PHD domain-mediated E3 ligase activity directs intramolecular sumoylation of an adjacent bromodomain required for gene silencing.

Tandem PHD and bromodomains are often found in chromatin-associated proteins and have been shown to cooperate in gene silencing. Each domain can bind specifically modified histones: the mechanisms of cooperation between these domains are unknown. We show that the PHD domain of the KAP1 corepressor functions as an intramolecular E3 ligase for sumoylation of the adjacent bromodomain.

Ku70 is stabilized by increased cellular SUMO.

Ku70 is a protein that finds itself at the heart of several important cellular processes. It is essential to the non-homologous end joining pathway as a part of the DNA-end binding complex, required for proper maintenance of telomeres and contributes to DNA damage recognition and regulation of apoptosis. Forces that regulate Ku70 are therefore likely to have large consequences on the physiologic state of the cell.

SUMO modification of human XRCC4 regulates its localization and function in DNA double-strand break repair.

The nonhomologous end-joining (NHEJ) pathway is responsible for rejoining the majority of double-strand breaks in mammalian cells, including the programmed breaks introduced by V(D)J recombination. The regulation of the enzymatic activities associated with this recombination pathway is still largely unknown. Here we report that human XRCC4 (for X-ray cross-complementation group 4), a protein essential for NHEJ, is subject to posttranslational protein modification.

Recombination-activating gene proteins: more regulation, please.

Developing B and T cells assemble gene segments in order to create the variable regions of immunoglobulin and T-cell receptors required by our adaptive immune response. The chemistry of this recombination pathway requires a specific nuclease and a more general repair pathway for double-strand breaks. A complex of the recombination-activating gene 1 (RAG1) and RAG2 proteins provides the nuclease activity.

Impaired V(D)J recombination and lymphocyte development in core RAG1-expressing mice.

RAG1 and RAG2 are the lymphocyte-specific components of the V(D)J recombinase. In vitro analyses of RAG function have relied on soluble, highly truncated "core" RAG proteins. To identify potential functions for noncore regions and assess functionality of core RAG1 in vivo, we generated core RAG1 knockin (RAG1(c/c)) mice.