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Mutations in all the right places
Children’s Hospital Boston and Howard Hughes Medical Institute (HHMI) researcher Frederick Alt, PhD (pictured, right), continues to work at the intersection of two fields: immunology and cancer. In the July 25 online edition of Nature, Alt and colleagues explain a mysterious phenomenon: the immune-system cells known as B lymphocytes undergo gene mutations that enable them to make an endless variety of customized antibodies, yet they remain protected from random mutations that could lead to cancer. An enzyme called activation-induced cytidine deaminase (AID) is required for the selective mutations, but until now, nobody knew how it mutates the “right” stretches of DNA while sparing the rest of the genome. Alt’s group reports that another molecule, known as replication protein A (RPA), directs AID to its proper target—the stretch of the B cell’s genome that directs antibody formation. “Without a targeting mechanism for AID, we’d be immunodeficient,” Alt says.

The discovery could also lead to strategies for preventing lymphomas, notes Jayanta Chaudhuri, PhD (pictured, left), the study’s first author and a postdoctoral fellow in the Division of Molecular Medicine. “We believe some mechanism prevents AID-RPA from going to regions of DNA that should not undergo mutations.”

Nerve cells: making connections
CHB and HHMI investigator David Clapham, MD, is shedding new light on how brain cells make the connections key to learning. One study, in the July 18 online edition of Nature Cell Biology, helps explain how a developing nerve cell “knows” what direction to grow in. Long extensions called dendrites grow outward from the cell body, navigating—sometimes great distances—to connect with other nerve cells. “Growth cones” at the dendrites’ leading edge guide them in the appropriate direction. Clapham’s team has found an unusual channel inside the nerve cell that comes to the surface when stimulated by a growth factor. The channel lets calcium into the cell, causing the growth cone to retract and possibly changing the direction of the advancing dendrite. The channel’s “just in time” appearance may allow nerve cells to adjust their response to incoming cues. Vassilios Bezzerides, an MD-PhD student in Clapham’s lab, was the study’s first author.

A second report, in the August 18 Neuron, describes a cluster of proteins that Clapham, first author Grigory Krapivinsky, PhD, and colleagues have found in synapses—the junctions between nerve cells where information is exchanged. One key protein, called SynGAP, helps increase the production of cell receptors involved in learning and long-term memory formation. It’s believed that the more of these receptors there are, the more indelible the memory.