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Unusual Protein Translation In Nijmegen Breakage Syndrome

  April, 5 2001 4:05
your information resource in human molecular genetics
Nijmegen breakage syndrome (NBS) is a rare chromosomal-instability syndrome associated with cancer predisposition and higher sensitivity to radiation. Most people with NBS carry a small deletion in the gene NBS1, resulting in a truncated protein product. Normally, the NBS1 protein binds to other proteins (binding partners) to control the cell cycle. The truncated protein, however, cannot interact with these binding partners, and so the seminal deletion is predicted to result in a complete loss of protein function. Curiously, however, people with NBS are viable (by definition), whereas mice that lack NBS1 are not. This has led some to suspect that the deletion mutation might somehow be unusual.

A research team led by John Petrini (of University of Wisconsin, Madison) set out to determine whether, and how, this could be. They observed that the cells of people with NBS not only contain the truncated fragment of NBS1, but also, a larger fragment encoded by NBS1 (Nature Genetics, Vol. 27, Issue 4, 01 April 2001). They went on to show that the shorter fragment results from the translation of the first portion of the NBS1 messenger RNA (mRNA), and the longer fragment derives from the remaining portion of the same mRNA. They demonstrate that is made possible by the small deletion, which results in the creation of a DNA motif called an 'internal ribosomal entry site' (IRES). The ribosome is a piece of cellular machinery that scans the genetic code carried by the mRNA and assembles the amino acid building blocks into a corresponding protein. Usually, it engages mRNA at one terminus, only disengaging when it comes to the end, or if its passage is disrupted by a mutation--for example, the NBS1 deletion. Thanks to the IRES, the ribosome is thought to re-engage in the middle of the mRNA, thus producing the larger protein fragment.

In contrast with the shorter fragment, the longer fragment is able to bind the usual partners of NBS1. Petrini and colleagues argue that this might permit partial rescue of NBS1 deficiency, which would account for the milder symptoms of people carrying the deletion. The IRES motif is common in bacteria, but this is this first time that one has been implicated in the pathology of a human disease.


Dr. John H. J. Petrini
University of Wisconsin Medical School
Genetics Bldg.
445 Henry Mall
Madison, WI 53706,
Tel: +1 608 265 6043
Fax : +1 608 262 2976
e-mail: jpetrini@facstaff.wisc.edu

Dr. Nahum Sonenberg
McGill University
Montreal, Quebec, Canada
Telephone: +1 (514) 398 7274
Fax: +1 (514) 398 7275
e-mail: sonenberg@medcor.mcgill.ca

(C) Nature Genetics press release.

Message posted by: Trevor M. D'Souza

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