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JCI online early table of contents: Dec. 1, 2010
Date:12/1/2010

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Kobe University Graduate School of Medicine, Kobe, Japan.
Phone: 81.78.382.5861; Fax: 81.78.382.2080; E-mail: takahash@med.kobe-u.ac.jp.

View this article at: http://www.jci.org/articles/view/44073?key=b3118ac5bf4c06518215


ONCOLOGY: From failed DNA repair, to altered energy generation, to tumor cell

Individuals with the genetic disorder xeroderma pigmentosum are extremely sensitive to light from the sun and have an increased risk of developing skin cancer. In a subset of individuals, the condition is caused by mutations in the XPC gene, which generates a protein known to be important in repairing damaged DNA. A team of researchers led by David Bickers, at Columbia University, New York, and Hamid Reza Rezvani, at INSERM U876, France have now provided new insight into how loss of XPC might lead to the formation of skin cancer in patients with xeroderma pigmentosum.

In the study, knocking down levels of XPC in human skin cells (keratinocytes) generated cells capable of causing skin cancer when injected into mice. Analysis of the cells showed that XPC knockdown led to the accumulation of damaged DNA. This, in turn, changed the way in which the keratinocytes generated energy such that they used the same energy-generating pathways used by cancer cells. This led to increased production of damaging molecules known as ROS, the gradual accumulation of mutations in mitochondrial DNA, and the formation of a tumor cell. These data delineate a new pathway by which mutations in a DNA repair gene can lead to tumor formation via effects on cellular energy generation.

TITLE: XPC silencing in normal human keratinocytes triggers metabolic alterations that drive the formation of squamous cell carcinomas

AUTHOR CONTACT:
David R. Bickers
College of Physicians and Surgeons
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Journal of Clinical Investigation
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