NYU School of Medicine pathology researchers solve another mystery in B lymphocyte d...( New York May 18 2009: A new study ...),Health

New York May 18, 2009: A new study published online in Nature Immunology ahead of the June 2009 print issue has found that homologous immunoglobulin (lg) alleles pair up in the nucleus at stages that coincide with V(D)J recombination of the heavy and light chain (Igh and Igk) loci. Researchers led by Jane A. Skok Ph.D., assistant professor in the Department of Pathology at NYU School of Medicine and a member of the NYU Cancer Institute, showed that the V(D)J recombinase, which consists of the RAG1 and RAG2 proteins, mediates this pairing and helps ensure that only one allele undergoes recombination at a time (a process known as allelic exclusion).

In "RAG-1 and ATM Coordinate Monoallelic Recombination and Nuclear Positioning of Immunoglobulin Loci," researchers found that RAG-mediated cleavage occurs on one allele at a time at every stage of Igh and Igk recombination; introduction of a double-strand break on one lg allele induces repositioning of its homologous partner to pericentromeric heterochromatin (a repressive compartment of the nucleus). This repositioning, surprisingly enough, depends on the DNA damage sensing factor ATM. It appears that cleavage activates ATM to act in trans on the uncleaved allele to reposition it in a repressive compartment of the nucleus, thereby preventing simultaneous recombination on both alleles and thus reducing the chance of translocations.

"This work deepens our understanding of the mechanisms that are in place for preventing translocations during V(D)J recombination that might ultimately lead to leukemias and lymphomas," says Skok. "It also helps us understand why individuals with a genetic deficiency in ATM suffer more cancers arising from such translocations."

Leukemias and lymphomas are very common cancers, especially in children. Chromosomal translocations involving the antigen receptor loci are a common underlying mechanism.

"V(D)J recombination plays a crucial rol
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