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ATM Modulates the Loading of Recombination Proteins onto a Chromosomal Translocation Breakpoint Hotspot

Chromosome translocations induced by DNA damaging agents, such as ionizing radiation and certain chemotherapies, alter genetic information resulting in malignant transformation. Abrogation or loss of the ataxia-telangiectasia mutated (ATM) protein, a DNA damage signaling regulator, increases the inc...

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Autores principales: Sun, Jiying, Oma, Yukako, Harata, Masahiko, Kono, Kazuteru, Shima, Hiroki, Kinomura, Aiko, Ikura, Tsuyoshi, Suzuki, Hidekazu, Mizutani, Shuki, Kanaar, Roland, Tashiro, Satoshi
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2965082/
https://www.ncbi.nlm.nih.gov/pubmed/21048951
http://dx.doi.org/10.1371/journal.pone.0013554
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author Sun, Jiying
Oma, Yukako
Harata, Masahiko
Kono, Kazuteru
Shima, Hiroki
Kinomura, Aiko
Ikura, Tsuyoshi
Suzuki, Hidekazu
Mizutani, Shuki
Kanaar, Roland
Tashiro, Satoshi
author_facet Sun, Jiying
Oma, Yukako
Harata, Masahiko
Kono, Kazuteru
Shima, Hiroki
Kinomura, Aiko
Ikura, Tsuyoshi
Suzuki, Hidekazu
Mizutani, Shuki
Kanaar, Roland
Tashiro, Satoshi
author_sort Sun, Jiying
collection PubMed
description Chromosome translocations induced by DNA damaging agents, such as ionizing radiation and certain chemotherapies, alter genetic information resulting in malignant transformation. Abrogation or loss of the ataxia-telangiectasia mutated (ATM) protein, a DNA damage signaling regulator, increases the incidence of chromosome translocations. However, how ATM protects cells from chromosome translocations is still unclear. Chromosome translocations involving the MLL gene on 11q23 are the most frequent chromosome abnormalities in secondary leukemias associated with chemotherapy employing etoposide, a topoisomerase II poison. Here we show that ATM deficiency results in the excessive binding of the DNA recombination protein RAD51 at the translocation breakpoint hotspot of 11q23 chromosome translocation after etoposide exposure. Binding of Replication protein A (RPA) and the chromatin remodeler INO80, which facilitate RAD51 loading on damaged DNA, to the hotspot were also increased by ATM deficiency. Thus, in addition to activating DNA damage signaling, ATM may avert chromosome translocations by preventing excessive loading of recombinational repair proteins onto translocation breakpoint hotspots.
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spelling pubmed-29650822010-11-03 ATM Modulates the Loading of Recombination Proteins onto a Chromosomal Translocation Breakpoint Hotspot Sun, Jiying Oma, Yukako Harata, Masahiko Kono, Kazuteru Shima, Hiroki Kinomura, Aiko Ikura, Tsuyoshi Suzuki, Hidekazu Mizutani, Shuki Kanaar, Roland Tashiro, Satoshi PLoS One Research Article Chromosome translocations induced by DNA damaging agents, such as ionizing radiation and certain chemotherapies, alter genetic information resulting in malignant transformation. Abrogation or loss of the ataxia-telangiectasia mutated (ATM) protein, a DNA damage signaling regulator, increases the incidence of chromosome translocations. However, how ATM protects cells from chromosome translocations is still unclear. Chromosome translocations involving the MLL gene on 11q23 are the most frequent chromosome abnormalities in secondary leukemias associated with chemotherapy employing etoposide, a topoisomerase II poison. Here we show that ATM deficiency results in the excessive binding of the DNA recombination protein RAD51 at the translocation breakpoint hotspot of 11q23 chromosome translocation after etoposide exposure. Binding of Replication protein A (RPA) and the chromatin remodeler INO80, which facilitate RAD51 loading on damaged DNA, to the hotspot were also increased by ATM deficiency. Thus, in addition to activating DNA damage signaling, ATM may avert chromosome translocations by preventing excessive loading of recombinational repair proteins onto translocation breakpoint hotspots. Public Library of Science 2010-10-27 /pmc/articles/PMC2965082/ /pubmed/21048951 http://dx.doi.org/10.1371/journal.pone.0013554 Text en Sun et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Sun, Jiying
Oma, Yukako
Harata, Masahiko
Kono, Kazuteru
Shima, Hiroki
Kinomura, Aiko
Ikura, Tsuyoshi
Suzuki, Hidekazu
Mizutani, Shuki
Kanaar, Roland
Tashiro, Satoshi
ATM Modulates the Loading of Recombination Proteins onto a Chromosomal Translocation Breakpoint Hotspot
title ATM Modulates the Loading of Recombination Proteins onto a Chromosomal Translocation Breakpoint Hotspot
title_full ATM Modulates the Loading of Recombination Proteins onto a Chromosomal Translocation Breakpoint Hotspot
title_fullStr ATM Modulates the Loading of Recombination Proteins onto a Chromosomal Translocation Breakpoint Hotspot
title_full_unstemmed ATM Modulates the Loading of Recombination Proteins onto a Chromosomal Translocation Breakpoint Hotspot
title_short ATM Modulates the Loading of Recombination Proteins onto a Chromosomal Translocation Breakpoint Hotspot
title_sort atm modulates the loading of recombination proteins onto a chromosomal translocation breakpoint hotspot
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2965082/
https://www.ncbi.nlm.nih.gov/pubmed/21048951
http://dx.doi.org/10.1371/journal.pone.0013554
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