DNA can be damaged by different environmental insults, such as ultraviolet light, ionizing radiation, oxidative stress or certain drugs. If the DNA is not repaired, cells may begin growing uncontrollably, leading to the development of cancer. Therefore, cells must maintain an intricate regulatory network to ensure that their DNA remains intact. Moffitt Cancer Center researchers have discovered a novel mechanism that controls a cell's response to DNA damage.
The protein SIRT1 plays an important role in controlling DNA damage. It can sense the presence of DNA damage, signal to other proteins that damage exists, aid in the repair of damage and stimulate cell death if the damage cannot be repaired.
Moffitt researchers found that SIRT1 is modified by a process called ubiquitination, in which a small residue called ubiquitin is added to SIRT1. This modification allows SIRT1 to relay information about DNA damage to other proteins, leading to either DNA repair or cell death.
The researchers performed studies to determine how ubiquitin modification changes SIRT1 function. They discovered that cells respond to ubiquitin modification of SIRT1 differently according to the type of environmental insult that occurs. If cells are exposed to a drug called etoposide, SIRT1 ubiquitination blocks cell death. However, if cells are exposed to oxidative stress, SIRT1 ubiquitination promotes cell death.
These results are important because they increase scientists' understanding of how proteins and cells function, potentially leading to more effective therapeutic drugs in the future.
"SIRT1 is known to be abnormally expressed in a variety of cancers and might be a good target for therapy. Ubiquitin-proteasome inhibitors have already been successfully used in cancer therapy and clinical trials. Therefore, this research might provide molecular bases and insights for developing additional therapeutic strategies in the future," explained Ed Seto, Ph.D., senior member of the Cancer Biology and Evolution Program at Moffitt.
The research was published in the Feb. 10 online edition of The Journal of Biological Chemistry.
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Journal of Biological Chemistry, www.jbc.org/content/290/14/8904.full.pdf+html