Cell Report: Scientists discover key enzymes that control telomere length
[Introduction] Since the discovery of telomerase in 1984, research efforts to identify other biomolecules that prolong or shorten the protective cap at the end of this chromosome have been slowly progressing. Now, researchers from Johns Hopkins University have discovered another key enzyme that is critical for maintaining telomere length.
Since the discovery of telomerase in 1984, research efforts to identify other biomolecules that prolong or shorten the protective cap at the end of this chromosome have been slow. Now, researchers from Johns Hopkins University have discovered another key enzyme that is critical for maintaining telomere length. Researchers say the new method they found to use the enzyme should speed up the discovery of other proteins and processes that determine telomere length. The findings were published in the November 14 issue of Cell Reports.
Dr. Carol Greider, director and professor of molecular biology and genetics at the Johns Hopkins University Institute of Basic Biomedical Sciences, said: "We have known for a long time that telomerase cannot tell the complete story of the telomere maintaining a certain length, but Using the tools we have, it's hard to figure out which proteins are responsible for telomerase to do its job.” Greider won the 2009 Nobel Prize in Physiology or Medicine for discovering telomerase.
Greider pointed out that clarifying the proteins necessary to extend telomeres has broad health effects because shortened telomeres are associated with various diseases such as aging and lung and bone marrow diseases, while too long telomeres are associated with cancer. Since telomeres are naturally shortened each time DNA replication is prepared for cell division, the cells need a well-regulated process to add the appropriate number of components to the telomeres throughout the life of the organism.
However, until now, researchers have been able to determine whether a particular protein is involved in maintaining telomere length through a limited and time-consuming test. This test first requires the blocking of suspected proteins in laboratory cultured cells. The effect is then allowed to grow and divide in approximately 3 months to ensure that the detected difference in telomerase length can occur. In addition to being time consuming, this test does not apply to the loss of protein that kills cells three months ago.
In order to find a better tool, Greider Lab graduate student Stella Suyong Lee initially used a method for measuring the telomere length of yeast. It is artificially cutting the mammalian telomeres and then detecting the telomerase-extended part - it takes less than a day to complete the test even if the blocked protein is necessary for cell division. But the transition from yeast to mammals involves a host of unforeseen technical difficulties, and the project lasted nearly five years. Greider attributes its ultimate success to Lee's insistence.
When they tried to run this new test called ADDIT, the Greider team tested an enzyme, ATM kinase. "ATM kinase is known to be involved in DNA repair, but there is no consensus on whether it plays a role in telomere extension," Greider said. Her team blocked the enzyme in laboratory-cultured mouse cells and found that it did extend telomeres using ADDIT. They used traditional, up to 3 months of telomere testing to verify the results and reached the same conclusion.
The team also found that in normal mouse cells, a drug that blocks the PARP1 enzyme activates ATM kinase and stimulates telomere elongation. Greider said the findings provide proof of concept: drugs can be used to extend telomeres to treat short-telanged diseases, such as bone marrow failure. But she warns that unlike in mouse cells, PARP1 does not have the same telomere elongation effect in human cells.
The Greider team intends to use ADDIT to discover more information about the telomere-extended biochemical signaling pathways involved in ATM kinases and other signaling pathways that help determine telomere length. Lee said: "The potential application is very exciting. Finally, ADDIT can help us understand the mechanism by which cells balance between aging and cancer-uncontrolled cell growth, which will be very interesting."
(Jilin Qijian Biotechnology Co., Ltd. www.qjbio.com.cn)