Heads of Laboratories
Leon Hess Professor
Laboratory of Cell Biology and Genetics
The lab studies telomeres, protective elements at the ends of chromosomes critical for the stability and maintenance of genetic information. Flawed telomere function can cause genomic alterations found in cancer, and the gradual loss of telomeres contributes to the aging of human cells. de Lange seeks to understand how telomere protection is established and what happens when telomere function is lost during the early stages of tumor formation.
Research in the de Lange lab focuses on mammalian telomeres, which are made up of long arrays of double-stranded TTAGGG repeats that end in a single-stranded 3′ overhang. These telomeric repeats wither away in a shortening process associated with cell proliferation. Telomerase can counteract this attrition and stabilizes telomeres by adding back telomeric repeats. However, this enzyme is absent from most human somatic cells, which eventually die due to the depletion of their telomere reserve.
Cancer cells, on the other hand, usually reactivate telomerase to achieve unlimited proliferative potential. The goal of de Lange’s research is to understand how telomeres protect chromosome ends, and what happens when telomere function is lost during the early stages of tumorigenesis before telomerase is activated.
The lab identified a six-subunit protein complex, which they named shelterin, that specifically binds to telomeres. Using Cre-mediated conditional deletion in mouse embryo fibroblasts, de Lange and her colleagues determined the fate of telomeres lacking one or more of the six shelterin subunits. This work showed that cells lacking shelterin perceive their natural chromosome ends as sites of DNA damage.
Six distinct DNA damage response pathways are repressed by shelterin. Two DNA damage signaling pathways, initiated by the ATM and ATR checkpoint kinases, inappropriately respond to chromosome ends that lack shelterin. In addition, shelterin represses three DNA double-strand break repair pathways at telomeres as well as two types of nonhomologous end joining and homology-directed repair, which have detrimental outcomes at telomeres. Finally, shelterin protects telomeres against a sixth threat: the inappropriate resection of the telomeric DNA by nucleases.
de Lange’s group is now working to determine the mechanism by which each shelterin protein inhibits its designated pathway, and how loss of telomere protection contributes to genome instability in human cancer. The researchers provided a major mechanistic insight in identifying the t-loop structure of telomeres in which the single-stranded overhang is inserted in the double-stranded repeat array of the telomere, thereby hiding the telomere end from the DNA damage response. Recent data has shown that the TRF2 component of shelterin is required to establish or maintain this structure. Since TRF2 is responsible for the repression of the ATM kinase pathway and non-homologous end joining, it is likely that the t-loop structure is critical to prevent these two pathways from acting inappropriately on chromosome ends.
Doctoraal examen, 1981
University of Amsterdam and National Institute for Medical Research
Ph.D. in biochemistry, 1985
University of Amsterdam and The Netherlands Cancer Institute
University of California, San Francisco, 1985–1990
Assistant Professor, 1990–1994
Associate Professor, 1994–1997
Associate Director, Anderson Center for Cancer Research, 2006–2011
Director, Anderson Center for Cancer Research, 2011–
The Rockefeller University
Paul Marks Prize, 2001
Director’s Pioneer Award, National Institutes of Health, 2005
Massachusetts General Hospital Cancer Center Prize, 2008
Research Professor Award, American Cancer Society, 2010
Clowes Memorial Award, American Association for Cancer Research, 2010
Vilcek Prize, 2011
Vanderbilt Prize, 2012
Rosalind Franklin Award, National Cancer Institute, 2012
Dr. H.P. Heineken Prize, 2012
Breakthrough Prize, 2013
Katharine Berkan Judd Award, 2013
Jill Rose Award, 2013
Canada Gairdner International Award, 2014
Foreign Associate, National Academy of Sciences
National Academy of Medicine
American Academy of Arts and Sciences
American Association for the Advancement of Science
Associate Member, European Molecular Biology Organization
Royal Netherlands Academy of Arts and Sciences
Royal Holland Society for Sciences and Humanities
Maciejowski, J. et al. Chromothripsis and kataegis induced by telomere crisis. Cell 163, 1641–1654 (2015).
Lottersberger, F. et al. 53BP1 and the LINC complex promote microtubule-dependent DSB mobility and DNA repair. Cell 163, 880–893 (2015).
Doksani, Y. et al. Super-resolution fluorescence imaging of telomeres reveals TRF2-dependent t-loop formation. Cell 155, 345–356 (2013).
Wu, P. et al. Telomeric 3′ overhangs derive from resection by Exo1 and Apollo and fill-in by POT1b-associated CST. Cell 150, 39–52 (2012).
Sfeir, A. and de Lange, T. Removal of shelterin reveals the telomere end-protection problem. Science 336, 593–597 (2012).