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HRMECH SIGNED

Nucleases in homologous recombination: from basic principles to genome editing

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EC-Contrib. €

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Partnership

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 HRMECH project word cloud

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

attempt    guarantee    replication    blocks    proteins    initial    endonuclease    first    setup    spontaneously    human    activates    combinational    ogous    physiological    health    progeny    mechanism    outcome    dna    phosphorylation    breaks    collapse    diversity    converted    repair    protein    blocked    nucleolytic    nucleases    genetic    division    radio    cas9    junction    ex    nuclease    conjunction    basic    gen    tend    mrx    eration    reproduction    mlh3    strand    molecules    dependent    initiates    joint    meiotic    mre11    unknown    infor    sexual    meiosis    xrs2    crispr    ing    regulated    efficiency    mlh1    processed    course    instrumental    plays    intermediates    prophase    function    recombination    holliday    cerevisiae    exchange    tentionally    genome    crossover    mechanisms    re    activating    molecular    viewpoint    editing    programmed    rad50    anistic    gained    previously    fork    paternal    direct    promotes    homol    near    chemotherapy    sae2    manner    maternal    homologous    mation    biochemical    ends    preferentially    crossovers    machinery    mech    resection   

Project "HRMECH" data sheet

The following table provides information about the project.

Coordinator
FONDAZIONE PER L ISTITUTO DI RICERCA IN BIOMEDICINA 

Organization address
address: VIA VINCENZO VELA 6
city: BELLINZONA
postcode: 6500
website: http://www.irb.usi.ch

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 Switzerland [CH]
 Project website https://www.irb.usi.ch/nucleases-homologous-recombination-basic-principles-genome-editing-hrmech
 Total cost 1˙999˙014 €
 EC max contribution 1˙999˙014 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2015-CoG
 Funding Scheme ERC-COG
 Starting year 2016
 Duration (year-month-day) from 2016-10-01   to  2021-09-30

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    FONDAZIONE PER L ISTITUTO DI RICERCA IN BIOMEDICINA CH (BELLINZONA) coordinator 1˙999˙014.00

Map

 Project objective

Homologous recombination plays a crucial role to repair DNA strand breaks that may occur spontaneously upon replication fork collapse, during the course of radio- or chemotherapy or in a programmed manner during meiosis. Understanding the molecular mechanisms of re-combinational repair is thus very important not only from a basic research viewpoint, but it is also highly relevant for human health. Here, we will define the function of nucleases in homol-ogous recombination. First, we will study the initial steps in this pathway. We could show previously that the S. cerevisiae Sae2 protein promotes the endonuclease activity of the Mre11-Rad50-Xrs2 (MRX) complex near protein blocked DNA ends. This initiates nucleolytic resection of DNA breaks and activates homologous recombination. Our biochemical setup will be instrumental to define how is the activity of Sae2 regulated by phosphorylation on a mech-anistic level and how physiological protein blocks direct the Mre11 endonuclease. We will ex-tend the study to the human system, and attempt to apply the gained knowledge to improve the efficiency of genome editing by activating recombination in conjunction with the CRISPR-Cas9 nuclease system. Second, we will study how homologous recombination promotes gen-eration of genetic diversity during sexual reproduction. DNA strand breaks are introduced in-tentionally during the prophase of the first meiotic division. They are then processed by the recombination machinery into Holliday junction intermediates. These joint molecules are preferentially converted into crossovers in meiosis, resulting in exchange of genetic infor-mation between the maternal and paternal DNA molecules. This is dependent on the Mlh1-Mlh3 nuclease through a yet unknown mechanism. We will study how Mlh1-Mlh3 in complex with other proteins guarantee crossover outcome to promote diversity of the progeny.

 Publications

year authors and title journal last update
List of publications.
2019 Lepakshi Ranjha, Maryna Levikova, Veronika Altmannova, Lumir Krejci, Petr Cejka
Sumoylation regulates the stability and nuclease activity of Saccharomyces cerevisiae Dna2
published pages: , ISSN: 2399-3642, DOI: 10.1038/s42003-019-0428-0
Communications Biology 2/1 2019-11-15
2019 Kristina Kasaciunaite, Fergus Fettes, Maryna Levikova, Peter Daldrop, Roopesh Anand, Petr Cejka, Ralf Seidel
Competing interaction partners modulate the activity of Sgs1 helicase during DNA end resection
published pages: , ISSN: 0261-4189, DOI: 10.15252/embj.2019101516
The EMBO Journal 38/13 2019-11-15
2018 Elda Cannavo, Dominic Johnson, Sara N. Andres, Vera M. Kissling, Julia K. Reinert, Valerie Garcia, Dorothy A. Erie, Daniel Hess, Nicolas H. Thomä, Radoslav I. Enchev, Matthias Peter, R. Scott Williams, Matt J. Neale, Petr Cejka
Regulatory control of DNA end resection by Sae2 phosphorylation
published pages: , ISSN: 2041-1723, DOI: 10.1038/s41467-018-06417-5
Nature Communications 9/1 2019-08-30
2017 Giordano Reginato, Elda Cannavo, Petr Cejka
Physiological protein blocks direct the Mre11–Rad50–Xrs2 and Sae2 nuclease complex to initiate DNA end resection
published pages: 2325-2330, ISSN: 0890-9369, DOI: 10.1101/gad.308254.117
Genes & Development 31/23-24 2019-08-30
2018 Giuseppina D’Alessandro, Donna Rose Whelan, Sean Michael Howard, Valerio Vitelli, Xavier Renaudin, Marek Adamowicz, Fabio Iannelli, Corey Winston Jones-Weinert, MiYoung Lee, Valentina Matti, Wei Ting C. Lee, Michael John Morten, Ashok Raraakrishnan Venkitaraman, Petr Cejka, Eli Rothenberg, Fabrizio d’Adda di Fagagna
BRCA2 controls DNA:RNA hybrid level at DSBs by mediating RNase H2 recruitment
published pages: , ISSN: 2041-1723, DOI: 10.1038/s41467-018-07799-2
Nature Communications 9/1 2019-08-30
2018 Lepakshi Ranjha, Sean M. Howard, Petr Cejka
Main steps in DNA double-strand break repair: an introduction to homologous recombination and related processes
published pages: 187-214, ISSN: 0009-5915, DOI: 10.1007/s00412-017-0658-1
Chromosoma 127/2 2019-08-30
2017 Angelo Taglialatela, Silvia Alvarez, Giuseppe Leuzzi, Vincenzo Sannino, Lepakshi Ranjha, Jen-Wei Huang, Chioma Madubata, Roopesh Anand, Brynn Levy, Raul Rabadan, Petr Cejka, Vincenzo Costanzo, Alberto Ciccia
Restoration of Replication Fork Stability in BRCA1- and BRCA2-Deficient Cells by Inactivation of SNF2-Family Fork Remodelers
published pages: 414-430.e8, ISSN: 1097-2765, DOI: 10.1016/j.molcel.2017.09.036
Molecular Cell 68/2 2019-08-30
2019 Petr Cejka
Seeing is believing: DNA zipping promotes DNA repair
published pages: 3321-3322, ISSN: 0021-9258, DOI: 10.1074/jbc.h119.007814
Journal of Biological Chemistry 294/9 2019-08-30
2019 Elda Cannavo, Giordano Reginato, Petr Cejka
Stepwise 5′ DNA end-specific resection of DNA breaks by the Mre11-Rad50-Xrs2 and Sae2 nuclease ensemble
published pages: 5505-5513, ISSN: 0027-8424, DOI: 10.1073/pnas.1820157116
Proceedings of the National Academy of Sciences 116/12 2019-08-30
2019 Roopesh Anand, Arti Jasrotia, Diana Bundschuh, Sean Michael Howard, Lepakshi Ranjha, Manuel Stucki, Petr Cejka
NBS1 promotes the endonuclease activity of the MRE11‐RAD50 complex by sensing CtIP phosphorylation
published pages: e101005, ISSN: 0261-4189, DOI: 10.15252/embj.2018101005
The EMBO Journal 38/7 2019-08-30
2019 Elda Cannavo, Giordano Reginato, Petr Cejka
Stepwise 5′ DNA end-specific resection of DNA breaks by the Mre11-Rad50-Xrs2 and Sae2 nuclease ensemble
published pages: 5505-5513, ISSN: 0027-8424, DOI: 10.1073/pnas.1820157116
Proceedings of the National Academy of Sciences 116/12 2019-08-30
2019 Petr Cejka
Seeing is believing: DNA zipping promotes DNA repair
published pages: 3321-3322, ISSN: 0021-9258, DOI: 10.1074/jbc.h119.007814
Journal of Biological Chemistry 294/9 2019-08-30

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