February 2008 — The immune system’s powerful cellular mutation and repair processes
appear to offer important clues as to how lymphatic cancer develops,
Yale School of Medicine researchers report this week in Nature.
"The implications of these findings are considerable," said David Schatz, a Howard Hughes Medical Institute
investigator, professor of immunobiology at Yale, and senior author of
the study. "It now seems likely that anything that compromises the
function of these DNA repair processes could lead to widespread
mutations and an increased risk of cancer."
The lymph system
is made up of infection-fighting B cells. Schatz and his colleagues
examined the somatic hypermutation (SHM) process, which introduces
random mutations in B cells’ antibody genes to make them more effective
in fighting infection.
SHM occurs in two steps: First, a
mutation initiator, or activation-induced deaminase (AID), causes
genetic mutations. Second, DNA repair enzymes spot the changes and
begin making "sloppy" repairs, which lead to yet more mutations. The
two steps combined, Schatz said, present a major risk to genomic
Interestingly, these same repair enzymes recognize
mutations in many other types of genes in the B cells, but they fix the
genes in a precise, or, "high fidelity," manner.
Up until now
it was thought the risk to genomic stability was avoided for the most
part because the first step of the SHM process only happened in
antibody genes. But this study found that AID acts on many other genes
in B cells, including genes linked to lymphatic cancer and other
"And then we had another surprise," Schatz said.
"Most of these non-antibody genes do not accumulate mutations because
the repair, for whatever reason, is precise, not sloppy."
this means, Schatz said, is that researchers studying lymphatic cancer
must understand both the first and the second step-the original
mutations and then the repair process.
"If the precise, or
high fidelity, repair processes break down, this would unleash the full
mutagenic potential of the initial mutation, resulting in changes in
many important genes," Schatz said. "We hypothesize that exactly this
sort of breakdown of the repair processes occurs in the early stages of
the development of B cell tumors."
Source : Yale University