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TelMetab SIGNED

Telomere metabolism in Genome Stability and Disease

Total Cost €

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EC-Contrib. €

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Partnership

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 TelMetab project word cloud

Explore the words cloud of the TelMetab project. It provides you a very rough idea of what is the project "TelMetab" about.

regulation    subject    microscopy    damage    previously    ends    replication    dyskeratosis    compensation    composition    organismal    uncovered    shorten    contexts    unprecedented    mutated    fe    diseases    maintaining    unappreciated    specialised    causes    recombination    absence    onset    mechanistic    route    compromised    cell    mitigate    hence    extend    expression    regulator    give    lost    cellular    degradation    screens    cancer    promiscuous    function    nucleoprotein    repair    division    segregase    telomerase    dysfunction    crispr    critically    mutations    hhs    erc    expertise    establishing    senescence    atrx    progressively    p97    human    biochemistry    telomeres    immortalization    helicase    genome    inhibition    cycle    homeostasis    frequently    implicated    proteomic    resolution    re    super    syndrome    highlighting    exquisite    slx4ip    pich    protect    structures    congenita    hreidarrson    rtel1    vertebrate    quantitative    telomere    clinical    genetic    chromosome    employ    hoyeraal    interrogate    dna    multiple    induction   

Project "TelMetab" data sheet

The following table provides information about the project.

Coordinator
THE FRANCIS CRICK INSTITUTE LIMITED 

Organization address
address: 1 MIDLAND ROAD
city: LONDON
postcode: NW1 1AT
website: www.crick.ac.uk

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country United Kingdom [UK]
 Project website https://www.crick.ac.uk/research/labs/simon-boulton
 Total cost 2˙118˙431 €
 EC max contribution 2˙118˙431 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2016-ADG
 Funding Scheme ERC-ADG
 Starting year 2017
 Duration (year-month-day) from 2017-09-01   to  2022-08-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    THE FRANCIS CRICK INSTITUTE LIMITED UK (LONDON) coordinator 2˙118˙431.00

Map

 Project objective

Telomeres are specialised nucleoprotein structures that protect chromosome ends from degradation and promiscuous DNA repair activities. Critically short telomeres give rise to Dyskeratosis Congenita and Hoyeraal-Hreidarrson Syndrome (HHS), highlighting the clinical importance of maintaining telomeres. Telomeres also progressively shorten with each cell division, eventually triggering cellular senescence. Although telomerase is able to extend telomeres to solve the “end replication problem”, its re-expression is a major route to cancer cell immortalization. Hence, telomeres and telomerase must be subject to exquisite regulation to maintain telomere homeostasis and organismal function. We have previously implicated the Fe-S helicase RTEL1 in maintaining vertebrate telomeres, which is frequently mutated in HHS. In this ERC proposal, we will employ proteomic methods, super-resolution microscopy, biochemistry and genetic approaches to: i) investigate why telomerase is the cause of telomere dysfunction in the absence of Rtel1, ii) how RTEL1 is controlled during the cell cycle, and iii) how this process is compromised by Rtel1 mutations in HHS. By establishing quantitative PICh to interrogate telomere composition in unprecedented detail, we have uncovered an unappreciated compensation between RTEL1 and ATRX at telomeres and also identified SLX4IP as a key regulator of telomere recombination, which we will characterize at a mechanistic level. We will extend our expertise in quantitative PICh and genome-wide CRISPR screens to identify novel factors that respond to or are lost from telomeres as a result of: i) induction of DNA damage at telomeres, ii) inhibition of p97 segregase, and iii) the onset of senescence. Our proposal will lead to a greater understanding of the causes/consequences of telomere dysfunction in multiple contexts, the factors that mitigate these effects to maintain telomere homeostasis and how these processes are compromised in human diseases.

 Publications

year authors and title journal last update
List of publications.
2019 Justin B. Steinfeld, Ondrej Beláň, Youngho Kwon, Tsuyoshi Terakawa, Amr Al-Zain, Michael J. Smith, J. Brooks Crickard, Zhi Qi, Weixing Zhao, Rodney Rothstein, Lorraine S. Symington, Patrick Sung, Simon J. Boulton, Eric C. Greene
Defining the influence of Rad51 and Dmc1 lineage-specific amino acids on genetic recombination
published pages: 1191-1207, ISSN: 0890-9369, DOI: 10.1101/gad.328062.119
Genes & Development 33/17-18 2020-03-23
2020 Aleksandra Vančevska, Wareed Ahmed, Verena Pfeiffer, Marianna Feretzaki, Simon J Boulton, Joachim Lingner
SMCHD 1 promotes ATM ‐dependent DNA damage signaling and repair of uncapped telomeres
published pages: , ISSN: 0261-4189, DOI: 10.15252/embj.2019102668
The EMBO Journal 2020-03-23
2018 Roberto Bellelli, Ondrej Belan, Valerie E. Pye, Camille Clement, Sarah L. Maslen, J. Mark Skehel, Peter Cherepanov, Genevieve Almouzni, Simon J. Boulton
POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication
published pages: 112-126.e5, ISSN: 1097-2765, DOI: 10.1016/j.molcel.2018.08.043
Molecular Cell 72/1 2020-03-23
2018 Roberto Bellelli, Valerie Borel, Clare Logan, Jennifer Svendsen, Danielle E. Cox, Emma Nye, Kay Metcalfe, Susan M. O’Connell, Gordon Stamp, Helen R. Flynn, Ambrosius P. Snijders, François Lassailly, Andrew Jackson, Simon J. Boulton
Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis
published pages: 707-721.e7, ISSN: 1097-2765, DOI: 10.1016/j.molcel.2018.04.008
Molecular Cell 70/4 2020-03-23
2019 Grzegorz Sarek, Panagiotis Kotsantis, Phil Ruis, David Van Ly, Pol Margalef, Valerie Borel, Xiao-Feng Zheng, Helen R. Flynn, Ambrosius P. Snijders, Dipanjan Chowdhury, Anthony J. Cesare, Simon J. Boulton
CDK phosphorylation of TRF2 controls t-loop dynamics during the cell cycle
published pages: 523-527, ISSN: 0028-0836, DOI: 10.1038/s41586-019-1744-8
Nature 575/7783 2020-03-23
2019 Carlota Colomer, Pol Margalef, Alberto Villanueva, Anna Vert, Irene Pecharroman, Laura Solé, Mónica González-Farré, Josune Alonso, Clara Montagut, Maria Martinez-Iniesta, Joan Bertran, Eva Borràs, Mar Iglesias, Eduard Sabidó, Anna Bigas, Simon J. Boulton, Lluís Espinosa
IKKα Kinase Regulates the DNA Damage Response and Drives Chemo-resistance in Cancer
published pages: 669-682.e5, ISSN: 1097-2765, DOI: 10.1016/j.molcel.2019.05.036
Molecular Cell 75/4 2020-03-23
2019 Tatiana Garcia-Muse, U. Galindo-Diaz, M. Garcia-Rubio, J.S. Martin, J. Polanowska, N. O’Reilly, A. Aguilera, Simon J. Boulton
A Meiotic Checkpoint Alters Repair Partner Bias to Permit Inter-sister Repair of Persistent DSBs
published pages: 775-787.e5, ISSN: 2211-1247, DOI: 10.1016/j.celrep.2018.12.074
Cell Reports 26/3 2020-03-23
2018 Anna R. Poetsch, Simon J. Boulton, Nicholas M. Luscombe
Genomic landscape of oxidative DNA damage and repair reveals regioselective protection from mutagenesis
published pages: , ISSN: 1474-760X, DOI: 10.1186/s13059-018-1582-2
Genome Biology 19/1 2020-03-13
2018 Ana María León-Ortiz, Stephanie Panier, Grzegorz Sarek, Jean-Baptiste Vannier, Harshil Patel, Peter J. Campbell, Simon J. Boulton
A Distinct Class of Genome Rearrangements Driven by Heterologous Recombination
published pages: 292-305.e6, ISSN: 1097-2765, DOI: 10.1016/j.molcel.2017.12.014
Molecular Cell 69/2 2019-06-06
2018 Pol Margalef, Panagiotis Kotsantis, Valerie Borel, Roberto Bellelli, Stephanie Panier, Simon J. Boulton
Stabilization of Reversed Replication Forks by Telomerase Drives Telomere Catastrophe
published pages: 439-453.e14, ISSN: 0092-8674, DOI: 10.1016/j.cell.2017.11.047
Cell 172/3 2019-06-06

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