Replication stress induces micronuclei comprising of aggregated DNA double-strand breaks.
<h4>Background</h4>Micronuclei (MN) in mammalian cells serve as a reliable biomarker of genomic instability and genotoxic exposure. Elevation of MN is commonly observed in cells bearing intrinsic genomic instability and in normal cells exposed to genotoxic agents. DNA double-strand break...
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oai:doaj.org-article:a14cc6b58dd34a4cb19fe6d1772f66502021-11-18T06:55:42ZReplication stress induces micronuclei comprising of aggregated DNA double-strand breaks.1932-620310.1371/journal.pone.0018618https://doaj.org/article/a14cc6b58dd34a4cb19fe6d1772f66502011-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21525980/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Micronuclei (MN) in mammalian cells serve as a reliable biomarker of genomic instability and genotoxic exposure. Elevation of MN is commonly observed in cells bearing intrinsic genomic instability and in normal cells exposed to genotoxic agents. DNA double-strand breaks are marked by phosphorylation of H2AX at serine 139 (γ-H2AX). One subclass of MN contains massive and uniform γ-H2AX signals. This study tested whether this subclass of MN can be induced by replication stress.<h4>Principal findings</h4>We observed that a large proportion of MN, from 20% to nearly 50%, showed uniform staining by antibodies against γ-H2AX, a marker of DNA double-strand breaks (DSBs). Such micronuclei were designated as MN-γ-H2AX (+). We showed that such MN can be induced by chemicals that are known to cause DNA replication stress and S phase arrest. Hydroxyurea, aphidicolin and thymidine could all significantly induce MN-γ-H2AX (+), which were formed during S phase and appeared to be derived from aggregation of DSBs. MN-γ-H2AX (-), MN that were devoid of uniform γ-H2AX signals, were induced to a lesser extent in terms of fold change. Paclitaxel, which inhibits the disassembly of microtubules, only induced MN-γ-H2AX (-). The frequency of MN-γ-H2AX (+), but not that of MN-γ-H2AX (-), was also significantly increased in cells that experience S phase prolongation due to depletion of cell cycle regulator CUL4B. Depletion of replication protein A1 (RPA1) by RNA interference resulted in an elevation of both MN-γ-H2AX (+) and MN-γ-H2AX (-).<h4>Conclusions/significance</h4>A subclass of MN, MN-γ-H2AX (+), can be preferentially induced by replication stress. Classification of MN according to their γ-H2AX status may provide a more refined evaluation of intrinsic genomic instabilities and the various environmental genotoxicants.Bing XuZhaoliang SunZhaojian LiuHaiyang GuoQiao LiuHaiyan JiangYongxin ZouYaoqin GongJay A TischfieldChangshun ShaoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 4, p e18618 (2011) |
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Medicine R Science Q Bing Xu Zhaoliang Sun Zhaojian Liu Haiyang Guo Qiao Liu Haiyan Jiang Yongxin Zou Yaoqin Gong Jay A Tischfield Changshun Shao Replication stress induces micronuclei comprising of aggregated DNA double-strand breaks. |
| description |
<h4>Background</h4>Micronuclei (MN) in mammalian cells serve as a reliable biomarker of genomic instability and genotoxic exposure. Elevation of MN is commonly observed in cells bearing intrinsic genomic instability and in normal cells exposed to genotoxic agents. DNA double-strand breaks are marked by phosphorylation of H2AX at serine 139 (γ-H2AX). One subclass of MN contains massive and uniform γ-H2AX signals. This study tested whether this subclass of MN can be induced by replication stress.<h4>Principal findings</h4>We observed that a large proportion of MN, from 20% to nearly 50%, showed uniform staining by antibodies against γ-H2AX, a marker of DNA double-strand breaks (DSBs). Such micronuclei were designated as MN-γ-H2AX (+). We showed that such MN can be induced by chemicals that are known to cause DNA replication stress and S phase arrest. Hydroxyurea, aphidicolin and thymidine could all significantly induce MN-γ-H2AX (+), which were formed during S phase and appeared to be derived from aggregation of DSBs. MN-γ-H2AX (-), MN that were devoid of uniform γ-H2AX signals, were induced to a lesser extent in terms of fold change. Paclitaxel, which inhibits the disassembly of microtubules, only induced MN-γ-H2AX (-). The frequency of MN-γ-H2AX (+), but not that of MN-γ-H2AX (-), was also significantly increased in cells that experience S phase prolongation due to depletion of cell cycle regulator CUL4B. Depletion of replication protein A1 (RPA1) by RNA interference resulted in an elevation of both MN-γ-H2AX (+) and MN-γ-H2AX (-).<h4>Conclusions/significance</h4>A subclass of MN, MN-γ-H2AX (+), can be preferentially induced by replication stress. Classification of MN according to their γ-H2AX status may provide a more refined evaluation of intrinsic genomic instabilities and the various environmental genotoxicants. |
| format |
article |
| author |
Bing Xu Zhaoliang Sun Zhaojian Liu Haiyang Guo Qiao Liu Haiyan Jiang Yongxin Zou Yaoqin Gong Jay A Tischfield Changshun Shao |
| author_facet |
Bing Xu Zhaoliang Sun Zhaojian Liu Haiyang Guo Qiao Liu Haiyan Jiang Yongxin Zou Yaoqin Gong Jay A Tischfield Changshun Shao |
| author_sort |
Bing Xu |
| title |
Replication stress induces micronuclei comprising of aggregated DNA double-strand breaks. |
| title_short |
Replication stress induces micronuclei comprising of aggregated DNA double-strand breaks. |
| title_full |
Replication stress induces micronuclei comprising of aggregated DNA double-strand breaks. |
| title_fullStr |
Replication stress induces micronuclei comprising of aggregated DNA double-strand breaks. |
| title_full_unstemmed |
Replication stress induces micronuclei comprising of aggregated DNA double-strand breaks. |
| title_sort |
replication stress induces micronuclei comprising of aggregated dna double-strand breaks. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2011 |
| url |
https://doaj.org/article/a14cc6b58dd34a4cb19fe6d1772f6650 |
| work_keys_str_mv |
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