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Investigators observed that the so-called Tim-Tipin complex acts like an SOS, sending a signal throughout the nucleus of the cell to decrease the rate of replication of DNA. The study suggests that the complex mediates the inhibition of replicon initiation and DNA chain elongation in cells damaged by ultraviolet radiation.
A study published in Molecular and Cellular Biology in April 2007 found two proteins that may protect against the development of skin cancer.
"Mutations occur because of damage to DNA that has been induced through UV (ultraviolet) light," says William Kaufmann, Ph.D., a researcher, a professor of pathology and laboratory medicine, and a member of the Lineberger Comprehensive Cancer Center and the Center for Environmental Health and Susceptibility at the University of North Carolina, Chapel Hill.
"The question is, what is it about the UV light that drives the development of cancer?"
Indeed, ultraviolet radiation from sunlight damages DNA in skin cells.
"The photons coming from sunlight can cause dimerization of DNA bases," Dr. Kaufmann tells Dermatology Times.
Cyclobutane pyrimidine dimers and 6,4-pyrimidine-pyrimidone photoproducts are principal forms of DNA damage induced by UVB and UVC, according to Dr. Kaufmann. This damage can result in mutations that lead to skin cancer.
Before they divide to form daughters, cells first must replicate their DNA. What Dr. Kaufmann has discovered is a protein complex, called the Tim-Tipin complex, which is required to inhibit the replication or copying of UV-damaged DNA.
The complex acts like an SOS, sending a signal throughout the nucleus of the cell to decrease the rate of replication. The decreased rate of replication increases the amount of time the cell has to repair its DNA, staving off cell death or development of cancerous properties in response to UV radiation.
Dr. Kaufmann notes that recent studies have examined the relationships among cell cycle checkpoints, recombinational repair and translesion synthesis machinery for preserving the integrity of replicating chromosomes.
What has been observed is that irreparable DNA damage, brought on by chemical damage to DNA in Saccharomyces cerevisiae, causes an uncoupling of leading and lagging strands. Extended regions of single-stranded DNA are produced as a result.
Studying DNA synthesis
In this study, investigators used immunofluorescence analysis to study DNA synthesis spread along DNA fibers.
HeLa cells were treated with 2.5 J/m2 ultraviolet radiation C. The treatment with UVC inhibited the initiation of new replicons and reduced the rate of chain elongation at active replication forks.
The depletion of Tim and Tipin reversed the ultraviolet-induced inhibition of replicon initiation, but influenced the rate of DNA synthesis at replication forks in different ways. Investigators found that in undamaged cells depleted of Tim, the apparent rate of replication fork progression was 52 percent of the control. The corollary: They found Tipin depletion had minimal or no impact on fork progression in unirradiated cells, but significantly weakened the UV-induced inhibition of DNA chain elongation.
The research suggests a model where the Tim-Tipin complex mediates the inhibition of replicon initiation and DNA chain elongation in cells damaged by ultraviolet radiation. The complex mediates the UV-induced intra-S checkpoint that protects against replication stress.
Dr. Kaufmann notes that scientists have known for a quarter of a century that a cell can prevent DNA replication from beginning when it detects damage in its own DNA. This research highlights the checkpoint mechanisms in the cell that provide the time to find and repair the damage, he adds.