Checkpoint Proteins Fail to Catch Subtle Errors

Cancer researchers have identified a mechanism that may explain how some errors in cell replication go undetected by the "checkpoint” monitoring proteins, which may result in aneuploidy (cells with an abnormal number of chromosomes) and the generation of tumors.

Investigators at the Massachusetts Institute of Technology (Cambridge, USA) used small interfering RNA (RNAi) technology to evaluate the function of proteins associated with the binding of chromosome kinetochores to spindle microtubules during cell replication. They found that RNAi-mediated depletion of the adenomatous polyposis coli (APC) protein and its binding partner, EB1, was unusual in affecting the movement and orientation of paired sister chromatids at the metaphase stage of cell division without apparently disturbing kinetochore-to-microtubule attachment.

The result was misalignment of the chromatid pairs causing chromosome misaggregation and aneuploidy. The checkpoint proteins that normally monitor the binding of chromosomes to microtubules failed to detect this misalignment. These findings were published in the June 8, 2006, online edition of EMBO (European Molecular Biology Organization).

"This is important because it is the first demonstration that interrupting the normal function of these proteins will cause the cell to become aneuploid,” said first author Dr. Viji Draviam, a research associate in the biology department of the Massachusetts Institute of Technology. "Our research sheds light on what could go wrong to cause an irregular number of chromosomes in cells even when the checkpoint proteins appear to be functioning properly.”



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