Damaged tumor suppressor plays major role in lymphoma development
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Scientists have known for years that chromosomal translocations — abnormalities in which a piece of one chromosome breaks off and fuses to another — lead to a type of blood cancer called lymphoma, but little was known about how cells accumulate translocations or defend themselves against them. Now, a team of researchers led by Rockefeller University’s Michel Nussenzweig and his brother Andre Nussenzweig, working at the National Cancer Institute, provide a crucial piece of evidence that answers this question.
Chromosomes mismatched. Scientists at Rockefeller and the National Cancer Institute have discovered that faulty tumor suppressor proteins can promote abnormalities in chromosomes that lead to blood cell cancers. Above, antibody-producing immune system B cells that have suffered chromosomal translocations, in which a piece of one chromosome (yellow) breaks off and fuses to another (blue). (Photo: Elsa Callen and Andre Nussenzweig, NCI.)
The research, reported as an advanced online publication by the journal Nature, implicates a malfunction in tumor suppressor proteins like p53 or p19 in the development of translocations induced by AID, a “genome destroyer” that initiates DNA damage.
“We wanted to know how AID leads to an accumulation of translocations in cancer cells and what normally protects cells from the accumulating translocations,” says Nussenzweig, Sherman Fairchild Professor and head of the Laboratory of Molecular Immunology at Rockefeller. “We now know that a mutation or decrease in the expression of the p53 gene facilitates the formation of translocations by AID.”
AID normally plays a crucial role in the body’s immune defense system by triggering two frequent events, class switch recombination and somatic hypermutation. Class switch recombination creates the different kinds of antibodies that B cells generate to protect the body from infection, while somatic hypermutation creates a tighter fit for the antibodies, which pick up foreign material in the body.
In the Nature paper, the scientists focused on the cellular events involved in class switch recombination. AID, activated by messages from the immune system, initiates breaks in the B cell’s DNA to trigger a recombination event, which produces antibodies with specialized functions. Breaking DNA can lead to translocations, however, including one involving an antibody heavy chain gene, and a cancer-causing gene called c-myc. Previous research by Nussenzweig and his colleagues showed that without AID, these translocations do not occur.
Cells use a trio of proteins to protect against DNA damage. A protein called ATM activates the p53 tumor suppressor in response to breaks in the double-stranded DNA. In the new study, Nussenzweig and his colleagues removed p53 and ATM from B cells, and found that these cells have much higher numbers of translocations, proving that ATM and p53 are essential for protecting B cells from translocations.
Under certain conditions, p53 can be activated by another tumor suppressor called p19. In B cells missing p19, higher numbers of translocations also were found, which suggests that p19 also protects against AID-induced translocations.
“We believe that the p19-p53 or ATM-p53 signaling axes may play complementary roles in eliminating incipient cancer cells during different stages of the translocation reaction,” says Nussenzweig.
Nussenzweig says that the findings also explain why combined mutations in p53 lead to cancer in mice. “If you knock out the normal resolution of class switch breaks, you eliminate the protective mechanism of p53, which results in an increase in cancer in mice,” says Nussenzweig.
