https://delangelab.org/labmembers daily 0.75 2025-09-22 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/1640108070850-5PB7H0C8M17OLI91VBVR/Titia.jpeg Lab Members https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/1640110382555-0FQ10YIGCN7DDZ82XMV9/Theo.jpg Lab Members https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/1640364229928-96QBTEVG6FCOM2W4XI84/Screen+Shot+2021-12-24+at+11.43.32+AM.png Lab Members https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/1641819029016-3TX3BNYCI31C49KUV83T/rosie.jpeg Lab Members https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/1641840394963-DU2YE84GFN0ENDUONY0S/Kaori.jpg Lab Members https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/1642103209879-12FS98C8XA6PE26MQZCW/george+headshot.jpg Lab Members https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/1642200900968-A3MKVJD323ZYZNTKCDIV/Hiro.jpeg Lab Members https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/9472a6ba-0d03-4993-91ce-2409678a82c7/IMG_3962.jpeg Lab Members https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/a92da3f9-8a09-43f1-8e22-605b195f8898/Yagmur.jpg Lab Members https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/9291fe4d-d46c-491c-a43b-cd4c8fe9e082/Adriana_2024.jpeg Lab Members https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/7e729264-8d86-47df-9e91-fc3eaaa00303/Jamie.jpeg Lab Members https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/39927a8a-dcce-4ede-9a32-23afc1dfb136/IMG_7816%5B18%5D.jpg Lab Members https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/cabfd3b4-8b2c-4b5f-b4a7-c618eec93940/image0.jpg Lab Members https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/04cd930a-4360-4c0c-a25b-a61208e74098/5e5ab3c9181777f1ecb566fcf5166de6+2.jpeg Lab Members https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/80e468f0-8156-4f2b-a482-14ee0d91df0f/Unknown.jpeg Lab Members https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/9897b56e-76d0-4167-b99c-d96f995531f9/Lab3b.jpg Lab Members https://delangelab.org/protocols daily 0.75 2023-07-24 https://delangelab.org/titia-de-lange daily 0.75 2024-09-23 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/3c8b2493-759a-4a23-9ae7-981ad82ee79c/Titia.jpeg Titia de Lange - Titia de Lange Leon Hess Professor American Cancer Society Professor Head of Laboratory of Cell Biology and Genetics Director, Anderson Center for Cancer Research https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/66978d3b-8385-4795-af60-8cd185cb951f/titia+2.jpeg Titia de Lange Tobias Keene, D.D.S. Hailing from Richmond, Virginia, Dr. Tobias Keene brings a bit of unabashed Southern hospitality to all his patients. He moved to Washington, D.C. over thirty years ago as a freshman at Ivy College. Right after graduation, he attended World University’s School of Dentistry. Before opening Keene Dental in 1994, he worked for free clinics and some of the finest practices in the District. He is part of the 123 Dental Association and stays up-to-date on the latest dental discoveries. When not striving to keep his patients happy and healthy, he’s enjoys hiking with his family in Rock Creek Park. https://delangelab.org/bokai-zhang daily 0.75 2025-09-05 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/5cbc06ed-e26e-42cd-ade6-6ffaf409f211/5e5ab3c9181777f1ecb566fcf5166de6+2.jpeg Bokai Zhang - Bio: Bokai is studying the mechanisms of replicative senescence. He enjoys creating fusion proteins for various tasks and talking about sequencing techniques. Outside of lab, he likes to draw digital illustrations. Education: BS. in Molecular, Cellular and Developmental Biology (University of Michigan, advisor: Ming Li, 2023) Publications: https://www.ncbi.nlm.nih.gov/myncbi/bokai.zhang.1/bibliography/public/ Awards and Fellowships: Program in Biology Director's award (Michigan) Underwood-Alger Scholarship (Michigan) https://delangelab.org/theo-bakker daily 0.75 2024-05-28 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/984bda13-572b-4b0a-a883-59ba29d16dc1/Theo.jpg Theo Bakker - Bio: Theo is studying the molecular mechanisms of telomere length regulation. He is interested in deciphering such mechanisms so that we can obtain a better understanding of diseases associated with telomere length aberrations. Education: BSc, Chemistry, University of St Andrews; 2018 MSc, Pharmacology, University of Oxford; 2019 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/c48cab3d-bd79-460e-a4f5-a1fa2219b424/theo+drink.png Theo Bakker https://delangelab.org/alexander-stuart daily 0.75 2024-08-13 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/16299c26-9c06-4448-be8e-02d193a553ba/Alex.jpeg Alexander Stuart - Bio: Alex is a cellular biologist interested in the molecular dynamics of aging cells. He is currently investigating the relationship between shelterin, senescence and cell behavior. Alex hopes to ensure our understanding of a fundamental question: what criteria allow a telomere to be recognized as "critically-short"? Education: Ph.D. (Rockefeller University, advisor Titia de Lange) B.S. in Biology, University of Michigan, 2017 https://delangelab.org/george-zakusilo daily 0.75 2024-05-28 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/ebac2de9-35ee-4456-9eb5-a1e4c63b99d2/george+headshot.jpg George Zakusilo - Bio: George Zakusilo is an MD-PhD student broadly interested in nucleic acid biology. He is currently pursuing aspects of telomere biology and DNA repair mechanisms that are unique to human cells. Publications: https://pubmed.ncbi.nlm.nih.gov/?term=George+Zakusilo+&sort=date Education: Ural Federal University B.A. in Biochemistry, CUNY Hunter College, 2016 Awards and fellowships : BSG-MSRP-Bio Gould Fellow (MIT) Jeff Wijnen Award (CUNY Hunter College) https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/30de2674-4c4d-4d63-bac9-63ebf502c927/george+extra.jpg George Zakusilo In the wild, you can find George sledding with his daughter or cooking and pretending to know how to play a guitar. https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/eb7c6795-b042-4d5e-aa88-61d57a0e8cfc/Hanifa+sleding.png George Zakusilo https://delangelab.org/hiro-takai daily 0.75 2024-05-29 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/c73f4698-65ce-4acb-bac2-a6912be9c48c/Hiro.jpeg Hiro Takai - Bio: Hiro Takai is a senior staff scientist in de Lange lab. He is interested in the regulation of telomere end processing. Education: PhD: The University of Tokyo Graduate School of Science, 1995 Post Doctoral Fellowships/Awards: Charles H. Revson Fellowship 2002-2003 Publications: https://www.ncbi.nlm.nih.gov/myncbi/hiroyuki.takai.1/bibliography/public/ https://delangelab.org/adriana-garzon daily 0.75 2024-05-28 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/3bc187d9-dac2-47a0-806b-e5781facefe4/Adriana2022.jpeg Adriana Garzon Bio: Adriana is the lab manager for the de Lange lab. She came to Rockefeller University as visiting student at the Chua Lab and later returned to her country to get her degree. She has worked as research assistant at the City College of New York and the Funabiki lab at Rockefeller University. Education: B.S Microbiology - Universidad de los Andes, Bogotá Colombia M.A Biology - City College of New York Outside the lab Adriana can be found running, exercising with her RU fitness pals, and starting new adventures with her daughter. https://delangelab.org/rosaura-mejia daily 0.75 2024-05-28 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/b6c7347e-fe0d-4583-990e-de5c87744cc7/rosie.jpeg Rosaura Mejia Bio: Rosie has been the lab helper for 12 years in the de Lange lab. Interests outside of the lab are exploring the city’s secret parks and gardens, going out with friends, and at home enjoying family time, cooking, and reading. https://delangelab.org/kaori-takai daily 0.75 2024-05-28 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/e8524ddd-6a3b-4c61-a725-9b2470c49351/Kaori.jpg Kaori Takai Bio: Kaori is a Research Specialist in the de Lange lab Education: M.S., Hunter College of the City University of New York, 2006 Publications: https://www.researchgate.net/scientific-contributions/Kaori-K-Takai-39411968 https://delangelab.org/publications daily 0.75 2025-11-11 https://delangelab.org/reagents daily 0.75 2022-02-07 https://delangelab.org/home-1 daily 1.0 2022-01-18 https://delangelab.org/research daily 0.75 2022-02-03 https://delangelab.org/contact daily 0.75 2022-11-27 https://delangelab.org/telomeres-and-cancer-tumor-suppression-and-genome-instability daily 0.75 2022-01-28 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/cae240c2-78ef-4899-bccb-9f24d7e6f1bc/Screen+Shot+2021-12-23+at+2.05.39+PM.png Telomeres and cancer: tumor suppression and genome instability - Lab members investigating Telomeres and Cancer: Alex Stuart and Charlie Kinzig Human telomeres can be maintained by telomerase, but most normal human cells lack (sufficient) telomerase and experience gradual telomere shortening. Eventually, the shortened telomeres become too short to fulfill their protective function, resulting in a block to further proliferation and a finite replicative lifespan. The critically short telomeres activate the DNA damage response (DDR), which induces cell cycle arrest and senescence or apoptosis, depending on the cellular context. This programmed proliferation barrier was long thought to function as a tumor suppressor pathway, a notion we recently confirmed based on cancer-prone families with mutations in TIN2. We showed that TIN2 is a haplo-insufficient tumor suppressor that limits telomere length at birth. Telomere shortening can only act as an effective tumor suppressor pathway if telomeres are not too long at birth. Mutations in the shelterin components TIN2 (shown by us) and POT1 (shown by others) result subjects with excessively long telomeres that are highly cancer prone. The work on the TIN2 and POT1 families demonstrate the protective power of the telomere tumor suppressor pathway in preventing cancer in many different tissues. Despite the telomere tumor suppressor pathway, cancer can develop when incipient cancer cells lose the p53/Rb pathways. Such cells ignore the cell cycle arrest signals and their telomeres shorten further during additional cell divisions. Eventually, the burden of dysfunctional telomeres leads to telomere-telomere fusions and formation of dicentric chromosomes. This stage of tumor development is referred to as telomere crisis and is thought to be an important source of genome instability in cancer. Eventually, patent cancer will only arise from cells that escape telomere crisis by upregulation of telomerase or activation of the ALT pathway. We are studying the genomic consequences of telomere crisis to understand how telomere shortening contributes to genome instability. Our work has illuminated that the persistent DNA damage signal associated with telomere dysfunction can drive endoreduplication and formation of tetraploid cells. Tetraploidization is a hallmark of a large fraction of human cancers and our work suggest that some of cancers have become tetraploid as a consequence of their past telomere crisis. We have also found that the dicentric chromosomes formed in telomere crisis can fuel chromothripsis (chromosome shattering) and kataegis (hyper mutation clusters). Unlike what was previously believed, we showed that dicentric chromosomes can persist through mitosis and form long chromatin bridges between daughter cells. These bridges are attacked by a cytoplasmic nuclease, TREX1, which accesses the bridge DNA after transient rupture of the nuclear envelope. TREX1 digestion leads to extensively fragmented ssDNA that joins the daughter nuclei after bridge resolution. The fragmented DNA is joined haphazardly leading to the chromothriptic patterns that are accompanied by kataegis due to APOBEC editing of the single stranded DNA. Publications since 2010: S.M. Dewhurst, X. Yao, J. Rosiene, H. Tian, J. Behr, N. Bosco, K.K. Takai, T. de Lange and M. Imieliński (2021) Structural variant evolution after telomere crisis. Nat Commun 12:2093. K. Hadi et al. (2020) Distinct Classes of Complex Structural Variation Uncovered across Thousands of Cancer Genome Graphs. Cell 183: 197-210.e32. C.A. Lovejoy, K. Takai, M.S. Huh, D.J. Picketts & T. de Lange (2020) ATRX affects the repair of telomeric DSBs by promoting cohesion and a DAXX-dependent activity. PLoS Biol 18: e3000594. J. Maciejowski, A. Chatzipli, A. Dananberg, K. Chu, E. Toufektchan, L.J. Klimczak, D.A. Gordenin, P.J. Campbell and T. de Lange. (2020) APOBEC3-dependent kataegis and TREX1-driven chromothripsis during telomere crisis. Nat Genet 52: 884-890. I. Schmutz, A.R. Mensenkamp, K.K. Takai, M. Haadsma, L. Spruijt, R.M. de Voer, S.S. Choo, F.K. Lorbeer, E.J. van Grinsven, D. Hockemeyer, M.C. Jongmans and T. de Lange (2020) TINF2 is a haploinsufficient tumor suppressor that limits telomere length. Elife 9:e61235 J. Maciejowski & T. de Lange (2017) Telomeres in cancer: tumour suppression and genome instability. Nat Rev Mol Cell Biol 18: 175-186. J. Maciejowski, Y. Li, N. Bosco, P.J. Campbell & T. de Lange (2015) Chromothripsis and Kataegis Induced by Telomere Crisis. Cell 163: 1641-1654. C.A. Lovejoy et al. For the ALT Starr Cancer Consortium. (2012) Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the Alternative Lengthening of Telomeres pathway. PLoS Genetics 8:e1002772 * corresponding author. T. Davoli and T. de Lange (2012) Telomere-driven tetraploidization occurs in human cells undergoing crisis and promotes transformation in mouse cells. Cancer Cell 21: 765-776. T. Davoli & T. de Lange (2011) The Causes and Consequences of Polypolidy in Normal Development and Cancer. Annu. Rev. Cell Dev. Biol, 27: 585-610 T. Davoli, E. Lazzerini Denchi, T. de Lange (2010) Persistent Telomere Damage Induces Bypass of Mitosis and Tetraploidy. Cell 141: 81-93. https://delangelab.org/how-shelterin-solves-the-endprotection-problem daily 0.75 2022-01-28 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/fb457d21-56ff-4224-ae42-8651d2a2b127/Screen+Shot+2021-12-23+at+2.10.13+PM.png How shelterin solves the end-protection problem - Lab members investigating How shelterin solves the end-protection problem: Nanda Sasi and Audrey Goldfarb: Molecular mechanisms of t-loop formation and ATM suppression by TRF2 John Zinder and Logan Myler: Structural aspects of human and mouse shelterin Overview The multi-subunit shelterin complex is crucial for the protection of telomeres from the DNA damage response and regulates telomere maintenance by telomerase. Shelterin is composed of six proteins: TRF1, TRF2, Rap1, TIN2, TPP1, and POT1. TRF1 and TRF2 bind to the duplex telomeric repeat array and anchor shelterin on telomeres. POT1 binds to single-stranded TTAGGG repeats and is recruited to telomeres through its interaction with TPP1. TPP1 in turns binds to TIN2, which interacts with both TRF1 and TRF2. Due to its specificity for the sequence and structure of the telomeric DNA, shelterin accumulates at the ends of human and mouse chromosomes but does not bind to DNA ends elsewhere in the genome. Thus, shelterin constitutes a unique marker of telomeres that allows cells to distinguish natural chromosome ends from sites of DNA damage. Our main approach to understanding how shelterin solves the end-protection problem is to generate mouse cells from which individual shelterin proteins can be removed using inducible systems, e.g. Cre-mediated deletion. Mouse and human shelterin are nearly identical except for the presence of two POT1 proteins (POT1a and POT1b) in mouse shelterin. Cre-mediated deletion of individual shelterin subunits showed that shelterin is highly compartmentalized such that distinct subunits are dedicated to different DDR pathways. TRF2 is critical for the repression of ATM signaling and prevents fusion of telomeres by the c-NHEJ and alt-NHEJ pathways. POT1 is needed to prevent the activation of the ATR kinase at telomeres. POT1a is primarily responsible for this function, whereas POT1b controls the formation of the 3’ overhang. TPP1 mediates the functions of POT1 by tethering POT1 via TIN2 to the rest of shelterin. The function of Rap1 is to repress Homology-Directed Repair (HDR) together with one of the two POT1 proteins. TRF1 has no direct role in protecting the chromosome end but is dedicated to promoting the replication of the telomeric DNA. Repression of ATM signaling and NHEJ by TRF2: t-loops Inappropriate NHEJ at telomeres can lead to unstable dicentric chromosomes and needs to be stringently repressed. NHEJ-mediated fusion of telomeres is rampant when TRF2 is deleted from mouse cells, resulting in long trains of joined chromosomes. The telomere fusions that occur in the absence of TRF2 are formed through the loading of the Ku70/80 heterodimer onto telomere ends and involve ligation by DNA ligase IV, indicating that they are due to c-NHEJ. Alternative-NHEJ, mediated by PARP1 and DNA ligase III can also take place at telomeres but only when shelterin is impaired in cells that lack the Ku70/80 heterodimer. Similarly, the activation of ATM signaling at telomeres needs to be averted. When TRF2 is deleted, most telomeres are recognized by the ATM kinase pathway, leading to DNA damage foci at telomeres (called Telomere Dysfunction Induced Foci or TIFs) that contain γ-H2AX, MDC1, 53BP1 and other DDR factors. ATM kinase activation at telomeres involves recognition of the telomere end by the Mre11/Rad50/Nbs1 (MRN complex). In collaboration with Jack Griffith (University of North Carolina, Chapel Hill) we found that telomeres can occur in a lariat conformation, referred to as the t-loop. T-loops are formed through the strand invasion of the 3’ telomeric overhang into the duplex part of the telomere. Since the discovery of t-loops in mammals, they have been found in many other eukaryotes, including protozoa, plants, and some fungi. Given that the telomere terminus is sequestered in the t-loop configuration we proposed that this structure would protect telomeres. Specifically, the t-loop structure would render telomeres impervious to c-NHEJ, which requires the loading of the Ku70/80 complex on free DNA ends, and would prevent the activation of the ATM kinase, which involves binding of the MRN complex to DNA ends. TRF2, the only shelterin protein required for the repression of c-NHEJ and ATM signaling, has the ability to make t-loops in vitro. We tested the TRF2/t-loop model by using super-resolution STORM imaging to detect t-loops in relaxed chromatin from cells with and without TRF2. The results demonstrated that TRF2, but not the other components of shelterin, is required for the establishment and/or maintenance of t-loops. Repression of ATR signaling by POT1 The constitutive ssDNA at telomeres can activate the ATR kinase. The ATR kinase signaling is activated through the binding of RPA to ssDNA and the Rad17-dependent loading of 9-1-1 on the neighboring 5’ ds/ss transition. ATR is recruited by ATRIP-dependent binding to RPA and is activated when TopBP1 interacts with the 9-1-1 complex. The 3’ overhang of mammalian telomeres is of sufficient length to bind RPA and ATR activation can occur if shelterin fails to protect the telomeres. The t-loop configuration does not protect telomeres from ATR signaling because all DNA structures needed for RPA binding and TopBP1-mediated ATR activation are present at the base of the t-loop. Shelterin uses POT1 to repress ATR signaling. In human shelterin, this task is delegated to the single POT1 protein, whereas mouse shelterin has two ATR repressors, POT1a and POT1b. When POT1a and POT1b are both deleted, ATR is activated at telomeres throughout the cell cycle. As expected, this activation is dependent on ATRIP and RPA. By binding to the ss telomeric DNA, POT1 blocks the accumulation of RPA at telomeres and thereby prevents ATR activation. As RPA is much more abundant than POT1 and since POT1 and RPA have the same affinity for telomeric sequences, the tethering of POT1 to the rest of shelterin is the critical aspect of its ability to exclude RPA from the ssDNA. Publications since 2010: L.R. Myler, C.G. Kinzig, N.K. Sasi, G. Zakusilo, S.W. Cai and T. de Lange (2021) The evolution of metazoan shelterin. Genes Dev 35:1625-1641. L.A. Timashev & T. de Lange (2020) Characterization of t-loop formation by TRF2. Nucleus 11: 164-177. K. Kratz & T. de Lange (2018) Protection of telomeres 1 proteins POT1a and POT1b can repress ATR signaling by RPA exclusion, but binding to CST limits ATR repression by POT1b. J Biol Chem: 293: 14384-14392. T. de Lange (2018) Shelterin-mediated telomere protection. Ann. Rev. Genetics 52:223-247. T. de Lange (2018) What I got wrong about shelterin. J. Biol. Chem. 293: 10453-10456. L.A. Timashev, H. Babcock, X. Zhuang & T. de Lange (2017) The DDR at telomeres lacking intact shelterin does not require substantial chromatin decompaction. Genes Dev 31: 578-589. I. Schmutz, L. Timashev, W. Xie, D.J. Patel & T. de Lange (2017) TRF2 binds branched DNA to safeguard telomere integrity. Nat. Struct. Mol. Biol.: 24:734-742. F. Erdel, K. Kratz, S. Willcox, J.D. Griffith, E.C. Greene & T. de Lange (2017) Telomere Recognition and Assembly Mechanism of Mammalian Shelterin. Cell Rep 18: 41-53. T. Kibe, M. Zimmermann & T. de Lange (2016) TPP1 Blocks an ATR-Mediated Resection Mechanism at Telomeres. Mol Cell 61: 236-246 Y. Doksani & T. de Lange (2016) Telomere-Internal Double-Strand Breaks Are Repaired by Homologous Recombination and PARP1/Lig3-Dependent End-Joining. Cell Rep. 17: 1646-1656. T. de Lange (2015) A loopy view of telomere evolution. Front. Genet. 6:321. S. Kabir, D. Hockemeyer, T. de Lange (2014). TALEN Gene Knockouts Reveal No Requirement for the Conserved Human Shelterin Protein Rap1 in Telomere Protection and Length Regulation. Cell Rep 9:1273-1280 D. Frescas, and T. de Lange (2014) Binding of TPP1 to TIN2 is required for POT1a,b-mediated telomere protection. J Biol Chem 289: 24180-24187. D. Frescas, and T. de Lange (2014) TRF2-Tethered TIN2 Can Mediate Telomere Protection by TPP1/POT1. Mol Cell Biol 34: 1349-1362. D. Frescas and T. de Lange (2014) A TIN2 dyskeratosis congenita mutation causes telomerase-independent telomere shortening in mice. Genes Dev. 28: 153-166. Y. Doksani*, J.Y. Wu*, T. de Lange, X. Zhuang (2013) Super-Resolution Fluorescence Imaging of Telomeres Reveals TRF2-Dependent T-Loop Formation. Cell 155: 345-356. *equal contribution A. Sfeir and T. de Lange (2012) Removal of shelterin reveals the telomere end-protection problem. Science 336: 593-597. K. Takai, T. Kibe, J. Donigian, D. Frescas and T. de Lange (2011) Telomere Protection by TPP1/POT1 Requires Tethering to TIN2. Mol. Cell, 44: 647-659. Y. Gong and T. de Lange (2010) A Shld1-controlled POT1a provides support for repression of ATR signaling at telomeres through RPA exclusion. Mol. Cell 40: 377-387. A. Sfeir, S. Kabir, M. van Overbeek, G.B. Celli, T. de Lange (2010) Loss of Rap1 induces telomere recombination in the absence of NHEJ or a DNA damage signal. Science 327: 1657-1661. T. Kibe, G.A. Osawa, C.E. Keegan, T. de Lange (2010) Telomere protection by TPP1 is mediated by POT1a and POT1b. Mol. Cell. Biol. 30: 1059-1066. K. Takai, S. Hooper, S. Blackwood, T. de Lange (2010) In Vivo stoichiometry of shelterin complex. J. Biol. Chem. 285: 1457-1467. https://delangelab.org/generation-and-maintenance-of-telomere-ends daily 0.75 2022-01-28 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/e846dfcd-97ff-4ef5-969f-ef9943bc403d/Screen+Shot+2021-12-23+at+3.28.57+PM.png Generation and maintenance of telomere ends - Lab members investigating the generation and maintenance of telomere ends: Hiro Takai: Regulation of telomere end processing and 3’ overhang formation Sarah Cai and John Zinder: Structure of CST-Pol alpha-primase George Zakusilo: The role of Ku at telomeres The protection of telomeres is in part dependent on the presence of a 3’ overhang at the telomere terminus. This overhang has to be regenerated every time telomeres are duplicated. Overhang generation is a complex process that involves multiple steps and the telomeres formed by leading- and lagging-strand DNA synthesis are processed differently as expected since their terminal structures are different immediately after DNA synthesis. The process of 3’ overhang formation is carefully controlled by shelterin. TRF2 recruits the Apollo nuclease, which is critical for an initial processing step at the leading-end telomeres. POT1b on the other hand, limits the length of the 3’ overhang by inhibiting Apollo. The Exo1 exonuclease also acts on telomere ends and excessive resection by Exo1 is also counteracted by POT1b. The latter regulation involves the interaction between POT1b and the CST (Ctc1, Stn1, Ten1) complex, which can promote Polymerase a/primase dependent fill-in reaction at telomere ends. Mice lacking POT1b show excessive telomere shortening, especially when telomerase is limiting. Ultimately, this telomere shortening evokes phenotypes reminiscent of Dyskeratosis congenita. A different inherited telomeropathy, Coats plus, is due to mutations in either CST or POT1, illustrating the importance of the interaction between shelterin and CST in the maintenance of sufficient telomere reserve. Publications Since 2010: Z. Mirman, N.K. Sasi, A. King, J.R. Chapman and T. de Lange (2022). 53BP1–shieldin-dependent DSB processing in BRCA1-deficient cells requires CST–Polα–primase fill-in synthesis. Nat Cell Biol 24, 51–61 Z. Mirman & T. de Lange (2020) 53BP1: a DSB escort. Genes Dev. 34: 7-23. Z. Mirman, F. Lottersberger, H. Takai, T. Kibe, Y. Gong, K. Takai, A. Bianchi, M. Zimmermann, D. Durocher & Titia de Lange (2018) 53BP1–RIF1–shieldin counteracts DSB resection through CST- and Polα-dependent fill-in. Nature: 560: 112-116. H. Takai, E. Jenkinson, S. Kabir, R. Babul-Hirji, N. Najm-Tehrani, D.A. Chitayat, Y.J. Crow & T. de Lange (2016) A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus. Genes Dev 30: 812-826. P. Wu, H. Takai and T. de Lange (2012) Telomeric 3' Overhangs Derive from Resection by Exo1 and Apollo and Fill-In by POT1b-Associated CST. Cell 150: 39-52. P. Wu, M. van Overbeek, S. Rooney, T. de Lange T. (2010) Apollo Contributes to G Overhang Maintenance and Protects Leading-End Telomeres. Mol. Cell. 39: 606-617. https://delangelab.org/trf1-promotes-telomere-replication-and-prevents-formation-of-fragile-telomeres daily 0.75 2022-01-28 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/27afffe2-4c50-42cd-9da5-0ad95ac3e4f7/Screen+Shot+2021-12-23+at+3.35.19+PM.png TRF1 promotes telomere replication and prevents formation of fragile telomeres - Lab members investigating the role of TRF1 at telomeres: Zhe Yang: Mechanisms of fragile telomere formation Deletion of TRF1 from mouse embryo fibroblasts revealed that TRF1 functions to promote efficient replication of telomeric DNA. In absence of TRF1, replication fork stalling occurs in telomeric DNA tracts and the ATR kinase pathway is activated at telomeres. In metaphase, telomeres appear as broken or decondensed, resembling the common fragile sites (CFS) observed after treatment with aphidicolin. Indeed, aphidicolin treatment also induces the fragile telomere phenotype, indicating that telomeres are similar to the CFS. Experiments with the BLM and RTEL1 helicases indicated that TRF1 cooperates with these factors to remove replication blocks from the telomeric DNA. We have proposed that TRF1 acts by removing G4 structures that can be formed in the TTAGGG repeats and might impede replication fork progression. Publications since 2009: Z. Yang, K.K. Takai, C.A. Lovejoy & T. de Lange (2020) Break-induced replication promotes fragile telomere formation. Genes Dev 34: 1392-1405. M. Zimmermann, T. Kibe, S. Kabir, T. de Lange (2014). TRF1 negotiates TTAGGG repeat-associated replication problems by recruiting the BLM helicase and the TPP1/POT1 repressor of ATR signaling. Genes Dev 28: 2477-2491. N. Bosco and T. de Lange (2012) A TRF1-controlled common fragile site containing interstitial telomeric sequences. Chromosoma 121: 465-474. A. Sfeir, S.T. Kosiyatrakul, D. Hockemeyer, S.L. MacRae, J. Karlseder, C.L. Schildkraut, T. de Lange (2009) Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. Cell.138:90-103. https://delangelab.org/emotional-support-team daily 0.75 2022-01-19 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/d6507ac2-f235-41e8-8763-47a1b9402ef1/John+and+Val.jpeg Emotional support team https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/f7908416-9e70-482a-b62d-346b1edbfe69/Screen+Shot+2021-12-24+at+8.38.36+AM.png Emotional support team https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/1641819648424-KJCR3BKE4HZ34UCJSTLK/cat1.jpg Emotional support team https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/1641819601641-NK60MLS62BETW1HEU09C/cat2.jpg Emotional support team https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/1b257688-1b90-4985-8e99-cdf617337552/bunny.JPG Emotional support team https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/1641819669757-3JE6V29BDEITFEXOPQQL/Ellie%2Band%2BFifi.jpg Emotional support team https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/2a358a0a-9d80-466a-9a6b-a41193f491ae/alex+dog.jpeg Emotional support team https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/f9ef6930-ed99-49a7-9563-b03deaff1ae2/titia+and+mike.jpeg Emotional support team https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/0c51ac91-af78-41f4-bc7c-bf5e2c92ba84/joe.jpeg Emotional support team https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/67fb45b8-ae2a-40ec-95b3-665508938261/mike+alphafold.jpeg Emotional support team https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/1c3fbf4d-d1c5-4d2d-9088-a7c584859a6d/Screen+Shot+2022-01-19+at+1.55.53+PM.png Emotional support team https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/1645711946992-DBBR67T2CRENOP6BLSUR/Val-Aud.jpg Emotional support team https://delangelab.org/stewart-barnes daily 0.75 2024-05-28 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/e30efac1-8585-496f-86dd-8e68212bfa68/Stew2.png Stewart Barnes - Bio: Stewart is the long-term Laboratory Administrator for the de Lange lab. He also serves as the Executive Assistant for Rockefeller’s Anderson Center for Cancer Research. Education: BA in Applied History/European Studies from Carnegie Mellon University Other interests: Outside the lab Stew can be found hiking, biking and kayaking through the wilds of northern New Jersey and southern New York state https://delangelab.org/pastpubs daily 0.75 2024-09-23 https://delangelab.org/departedsally daily 0.75 2022-02-04 https://delangelab.org/mefs daily 0.75 2022-02-07 https://delangelab.org/mouse-strains daily 0.75 2022-02-07 https://delangelab.org/publications-1 daily 0.75 2025-09-05 https://delangelab.org/lab-fun daily 0.75 2023-10-23 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/94b6f859-e3bf-4764-934c-b8f487a25227/img_4588_720.jpg Lab fun https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/9829a5df-3393-4a0a-bbe5-76f4ac9ea884/img_4586_720.jpg Lab fun https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/a7095e71-992f-46fc-a7db-856ecdb4ea6a/Group.JPG Lab fun https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/e2583696-9c99-4368-9f84-191327516a23/IMG_3283.JPG Lab fun https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/d24f8710-772a-410e-b5de-9df1c980c930/IMG_3271.JPG Lab fun https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/ba2d10dd-e272-41c6-8b2c-c3f3bd2b0778/IMG_5071.jpeg Lab fun https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/56e3d092-4579-498a-adae-70b22c5704d3/IMG_5066.jpeg Lab fun https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/3e9ae470-d34e-4567-8c50-9acb4d7bb519/IMG_3242.JPG Lab fun https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/18c60c11-b392-452a-895b-020b2237a874/LabPhoto_Library.jpg Lab fun https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/a50dcbe1-8f08-46ba-8fd5-484fe906b4d4/IMG_4784.jpeg Lab fun https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/d2aa3de3-f58d-44d4-92e6-72f393e99a9c/IMG_1566.JPG Lab fun https://delangelab.org/jamie-phipps daily 0.75 2024-05-28 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/2ecca202-a870-487d-aefc-aa8cba753a57/Jamie.jpg Jamie Phipps Bio: Jamie is using a combination of cell and molecular biology approaches to study the mechanisms that repress aberrant homologous recombination at telomeres. He’s also interested in the nature and regulation of telomeric sister chromatid cohesion. Publications: https://www.ncbi.nlm.nih.gov/myncbi/jamie.phipps.1/bibliography/public/ Education: PhD in Cell and Molecular Biology, University Paris-Saclay, 2024 MSc in Gene, Cell, Development, University Paris-Saclay, 2020 BSc in Biochemistry, Nottingham Trent University, 2017 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/1f04a1e4-66cc-40ed-9426-5f7294996071/image002.jpg https://delangelab.org/hannah-trost daily 0.75 2024-05-28 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/39927a8a-dcce-4ede-9a32-23afc1dfb136/IMG_7816%5B18%5D.jpg Hannah Trost - Bio: Hannah is interested in understanding aberrant repair of DNA double-strand breaks. She is currently studying the mechanisms of break-induced replication and neo-telomere formation. Education: 2024 - PhD in Molecular Biology, City of Hope Medical Center Advisor: Jeremy Stark 2016 - B.S. in Biochemistry, University of California, Los Angeles Publications: https://www.ncbi.nlm.nih.gov/myncbi/14qmfkv89qu15E/bibliography/public/ https://delangelab.org/nada-terra daily 0.75 2024-09-06 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/ee88fd09-94c6-4698-b84c-c16b2634e73d/image0.jpeg Nada Terra - Bio: Nada is interested in cell biology and tumorigenesis. Like Titia, she has previously studied mTOR, Myc, and trypanosomes. Now, she’s excited to explore the next natural trajectory: telomere biology. Outside of lab, Nada enjoys painting, listening to music, and drinking matcha. Publications: https://www.ncbi.nlm.nih.gov/myncbi/nada.terra.1/bibliography/public/ Education: B.A in Biology, Macaulay Honors College at CUNY Hunter College, 2020 Awards and Fellowships: Charlotte Hughes Devree Scholarship Award for Graduate Study (Hunter College, 2021) New York State Scholarship for Academic Excellence (2016-2020) Department of Biology Undergraduate Research Achievement Award (Hunter College, 2019) ABRCMS Oral Presentation Award (2019) Contact: nterra@rockefeller.edu https://delangelab.org/jinrou-li daily 0.75 2025-09-05 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/6c00d321-4a01-4b2e-b6a7-5ca1f896ad99/Unknown.jpeg Jinrou Li - Bio: Jinrou is fascinated by the fundamental molecular processes that govern telomere function. She is particularly interested in telomere maintenance mechanisms and telomere length regulation. Outside of lab, she is a big fan of Nintendo. Education: B.S. in Life Sciences, Peking University, 2024 Personal Website: jinrouli.github.io https://delangelab.org/giordano-reginato daily 0.75 2025-09-06 https://images.squarespace-cdn.com/content/v1/61c20b2946a75a2c2aafd075/9897b56e-76d0-4167-b99c-d96f995531f9/Lab3b.jpg Giordano Reginao - Bio: Giordano is interested in DNA damage repair. He is currently studying how the C-strand maintenance machinery is recruited to the telomeres. Education: 2021 - PhD in Biochemistry, ETH Zuriich 2017- MSc degrees in Cellular and Molecular Biology, University of Trento 2014 - BSc degrees in Cellular and Molecular Biology, University of Trento Publications: https://pubmed.ncbi.nlm.nih.gov/?term=giordano+reginato&sort=date Awards and Fellowships: 2024- present, Postdoc Mobility fellowship SNSF 2022 Silver Medal of ETH Zurich for Outstanding doctoral thesis 2019- 2020 IRB Student award, University of Trento