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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.
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