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Hanging Cancer on the Fulcrum of the Acidic Hinge

Roth Cell Reports Acidic Hinge blog post image genomic instability Sept 13Peter Nowell, David Hungerford, and Janet Rowley are famous for their contributions to understanding how translocations -- swaps of genetic bits between chromosomes – are the genomic basis for some blood cancers. This story of the Philadelphia Chromosome is now legendary.

Other blood cancers are also related to mutations that can cause translocations, for example ones in V(D)J recombinase, an enzyme responsible for cutting and pasting DNA to generate a diverse repertoire of antigen receptors for immune cells. This research also started decades ago, in the 1980s, by Phil Leder, Carlo Croce, and others, with the observation that certain B-cell lymphomas contain cancer-causing translocations that apparently result from errors in V(D)J recombination.

These converging lines of evidence just go to show that there are many types of cancer associated with chromosomal translocations, and likely more to be found.

Case in point - in a recent Cell Reports paper, the lab of David Roth, MD, PhD, chair of the Department of Pathology and Laboratory Medicine, at the Perelman School of Medicine, University of Pennsylvania, showed that a mutation in V(D)J recombinase causes genomic instability in cultured pre-B cells, precursors to mature immune cells. Double-strand breaks in DNA associated with V(D)J recombination are normally repaired with high fidelity by molecular machinery called the nonhomologous end-joining (NHEJ) protein.

Previous studies from the Roth lab showed that V(D)J recombinase (consisting of the RAG1 and RAG2 proteins) normally sends a newly made double-strand break down the correct DNA-repair path by preventing access to other, inappropriate repair mechanisms. This shepherding process can be disabled if the C-terminus end of the RAG2 subunit is removed, causing chromosome aberrations in developing immune cells and, in the absence of a working tumor suppressor p53, aggressive formation of lymphoma in mice.

The Cell Reports paper shows that altering just a few amino acids in a bend, or "hinge," in the enzyme, linking the C-terminus to the rest of the RAG2 protein, induces similar levels of genomic instability compared to the earlier study.

“In the new study, we discovered that certain mutations in the RAG2 subunit cause genomic instability in a mouse B-cell model,” Roth says. “Specifically, we show that decreasing the density of negative charges in a certain region termed the ‘acidic hinge,’ which is predicted to decrease the flexibility of the protein, causes accumulation of unrepaired or misrepaired chromosome breaks.”  

Structural changes to the enzyme -- obtained via computer algorithms that predict protein secondary structure based on the amino-acid sequence and experimental results -- support the team’s hypothesis that reduced flexibility of the acidic hinge underlies the genomic instability.

The team also looked in the human exome database and found naturally occurring sequence variants of RAG2 with single amino-acid changes in the acidic hinge.

“We noted that there are rare polymorphisms in humans that also decrease the density of negative charge in the subunit of the enzyme, and we show that these changes indeed cause genomic instability in mouse pre B cells,” says Roth.

ResearchBlogging.orgCoussens MA, Wendland RL, Deriano L, Lindsay CR, Arnal SM, & Roth DB (2013). RAG2's Acidic Hinge Restricts Repair-Pathway Choice and Promotes Genomic Stability. Cell reports, 4 (5), 870-8 PMID: 23994475

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