I. Telomeres and Human Disease
II. How Telomeres Solve the End-protection Problem
Part I: Telomeres and Human Disease
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In this seminar, Dr. Titia de Lange gives an overview of telomeres, the protective repeats at the ends of chromosomes. Because telomeres resemble double stranded DNA (dsDNA) breaks, they could be recognized by the DNA damage response (DDR) pathway leading to cell cycle arrest and genome instability. De Lange discusses the proteins that protect telomeres, how telomeres are maintained by telomerase, mechanisms of telomere shortening, and the role of telomere shortening in cancer and several inherited human diseases.
In her second lecture, de Lange describes the function of shelterin, the protein complex that binds to telomeres and prevents the recognition and activation of the DDR pathway. Important to this process are two shelterin proteins, TRF2 and POT1. TRF2 and POT1 block the activation of the DDR-initiating kinases, ATM and ATR, and prevent inappropriate DNA repair. De Lange explains that TRF2 blocks ATM signaling via the formation of an altered telomere structure called the t-loop. She also discusses the mechanism by which POT1 represses the activation of the ATR kinase.
Dr. Titia de Lange is the Leon Hess Professor, an American Cancer Society Research Professor, and the Director of the Anderson Center for Cancer Research at Rockefeller University. After getting her doctorate from the University of Amsterdam, she pursued her postdoctoral training with Dr. Harold Varmus at UCSF. Here, she isolated human telomeric DNA and was the first to show that tumor telomeres are shortened. She joined Rockefeller University as a Professor in 1990. At Rockefeller, her laboratory studies the mechanisms by which mammalian telomeres are protected from the DNA damage response.
For her scientific contributions, de Lange was elected foreign associate of the National Academy of Sciences (2006), and member of the Royal Dutch Academy of Sciences (2000), and the American Academy of Arts and Sciences (2007). She received the Paul Marks Prize for Cancer Research in 2000, the Breakthrough Prize in Life Sciences in 2013, and the Canada Gairdner International award in 2014. Learn more about Dr. de Lange’s research at her lab website.
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E. Lazzerini Denchi and T. de Lange (2007) Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature 448: 1068-1071.
W. Palm and T. de Lange (2008) How shelterin protects mammalian telomeres. Ann. Rev. Genetics 42: 301-334.
A. Sfeir and T. de Lange (2012) Removal of shelterin reveals the telomere end-protection problem. Science 336: 593-597.
Y. Doksani, et. al. (2013) Super-resolution fluorescence imaging of telomeres reveals TRF2-dependent t-loop formation. Cell 155: 345-356.
J. Maciejowski and T. de Lange (2017) Telomeres and genome instability in cancer. Nat. Rev. Mol. Biol., in press.