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Recognition of Double Strand Breaks by a Mutator Protein (MU2) in Drosophila melanogaster

Telomere capture, a rare event that stabilizes chromosome breaks, is associated with certain genetic abnormalities in humans. Studies pertaining to the generation, maintenance, and biological effects of telomere formation are limited in metazoans. A mutation, mu2(a), in Drosophila melanogaster decre...

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Autores principales: Dronamraju, Raghuvar, Mason, James M.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2672170/
https://www.ncbi.nlm.nih.gov/pubmed/19424425
http://dx.doi.org/10.1371/journal.pgen.1000473
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author Dronamraju, Raghuvar
Mason, James M.
author_facet Dronamraju, Raghuvar
Mason, James M.
author_sort Dronamraju, Raghuvar
collection PubMed
description Telomere capture, a rare event that stabilizes chromosome breaks, is associated with certain genetic abnormalities in humans. Studies pertaining to the generation, maintenance, and biological effects of telomere formation are limited in metazoans. A mutation, mu2(a), in Drosophila melanogaster decreases the rate of repair of double strand DNA breaks in oocytes, thus leading to chromosomes that have lost a natural telomere and gained a new telomere. Amino acid sequence, domain architecture, and protein interactions suggest that MU2 is an ortholog of human MDC1. The MU2 protein is a component of meiotic recombination foci and localizes to repair foci in S2 cells after irradiation in a manner similar to that of phosphorylated histone variant H2Av. Domain searches indicated that the protein contains an N-terminal FHA domain and a C-terminal tandem BRCT domain. Peptide pull-down studies showed that the BRCT domain interacts with phosphorylated H2Av, while the FHA domain interacts with the complex of MRE11, RAD50, and NBS. A frameshift mutation that eliminates the MU2 BRCT domain decreases the number and size of meiotic phospho-H2Av foci. MU2 is also required for the intra-S checkpoint in eye-antennal imaginal discs. MU2 participates at an early stage in the recognition of DNA damage at a step that is prerequisite for both DNA repair and cell cycle checkpoint control. We propose a model suggesting that neotelomeres may arise when radiation-induced chromosome breaks fail to be repaired, fail to arrest progression through meiosis, and are deposited in the zygote, where cell cycle control is absent and rapid rounds of replication and telomere formation ensue.
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spelling pubmed-26721702009-05-08 Recognition of Double Strand Breaks by a Mutator Protein (MU2) in Drosophila melanogaster Dronamraju, Raghuvar Mason, James M. PLoS Genet Research Article Telomere capture, a rare event that stabilizes chromosome breaks, is associated with certain genetic abnormalities in humans. Studies pertaining to the generation, maintenance, and biological effects of telomere formation are limited in metazoans. A mutation, mu2(a), in Drosophila melanogaster decreases the rate of repair of double strand DNA breaks in oocytes, thus leading to chromosomes that have lost a natural telomere and gained a new telomere. Amino acid sequence, domain architecture, and protein interactions suggest that MU2 is an ortholog of human MDC1. The MU2 protein is a component of meiotic recombination foci and localizes to repair foci in S2 cells after irradiation in a manner similar to that of phosphorylated histone variant H2Av. Domain searches indicated that the protein contains an N-terminal FHA domain and a C-terminal tandem BRCT domain. Peptide pull-down studies showed that the BRCT domain interacts with phosphorylated H2Av, while the FHA domain interacts with the complex of MRE11, RAD50, and NBS. A frameshift mutation that eliminates the MU2 BRCT domain decreases the number and size of meiotic phospho-H2Av foci. MU2 is also required for the intra-S checkpoint in eye-antennal imaginal discs. MU2 participates at an early stage in the recognition of DNA damage at a step that is prerequisite for both DNA repair and cell cycle checkpoint control. We propose a model suggesting that neotelomeres may arise when radiation-induced chromosome breaks fail to be repaired, fail to arrest progression through meiosis, and are deposited in the zygote, where cell cycle control is absent and rapid rounds of replication and telomere formation ensue. Public Library of Science 2009-05-08 /pmc/articles/PMC2672170/ /pubmed/19424425 http://dx.doi.org/10.1371/journal.pgen.1000473 Text en This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
spellingShingle Research Article
Dronamraju, Raghuvar
Mason, James M.
Recognition of Double Strand Breaks by a Mutator Protein (MU2) in Drosophila melanogaster
title Recognition of Double Strand Breaks by a Mutator Protein (MU2) in Drosophila melanogaster
title_full Recognition of Double Strand Breaks by a Mutator Protein (MU2) in Drosophila melanogaster
title_fullStr Recognition of Double Strand Breaks by a Mutator Protein (MU2) in Drosophila melanogaster
title_full_unstemmed Recognition of Double Strand Breaks by a Mutator Protein (MU2) in Drosophila melanogaster
title_short Recognition of Double Strand Breaks by a Mutator Protein (MU2) in Drosophila melanogaster
title_sort recognition of double strand breaks by a mutator protein (mu2) in drosophila melanogaster
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2672170/
https://www.ncbi.nlm.nih.gov/pubmed/19424425
http://dx.doi.org/10.1371/journal.pgen.1000473
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