TSRI Scientists Catch Misguided DNA-Repair Proteins in the Act

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Newswise LA JOLLA, CA May 22, 2014 Accumulation of DNA damage can cause aggressive forms of cancer and accelerated aging, so the bodys DNA repair mechanisms are normally key to good health. However, in some diseases the DNA repair machinery can become harmful. Scientists led by a group of researchers at The Scripps Research Institute (TSRI) in La Jolla, CA, have discovered some of the key proteins involved in one type of DNA repair gone awry.

The focus of the new study, published in the May 22, 2014 edition of the journal Cell Reports, is a protein called Ring1b. The TSRI researchers found that Ring1b promotes fusion between telomeresrepetitive sequences of DNA that act as bumpers on the ends of chromosomes and protect important genetic information. The scientists also showed inhibiting this protein can significantly reduce the burden on cells affected by such telomere dysfunction.

We are very far from therapy, but I think a lot of the factors weve identified could play key roles in processing dysfunctional telomeres, a key event in tumorigenesis [cancer initiation], said Eros Lazzerini Denchi, assistant professor at TSRI who led the study.

The Trouble with Telomeres

Humans are born with long telomeres, but these become shorter every time a cell in the body divides. With age, telomeres become very short, especially in tissues that have high proliferation rate.

Thats when the problems start. When telomeres become too short, they lose their telomere protective cap and become recognized by the DNA repair machinery proteins. This can lead to the fusion of chromosomes end-to-end into a string-like formation.

Joined chromosomes represent an abnormal genomic arrangement that is extremely unstable in dividing cells. Upon cell division, joined chromosomes can rupture, creating new break points that can further re-engage aberrant DNA repair. These cycles of fusion and breakage cause a rampant level of mutations that are fertile ground for cancer.

You basically scramble the genome, and then you have lots of chances to select very nasty mutations, said Lazzerini Denchi.

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TSRI Scientists Catch Misguided DNA-Repair Proteins in the Act