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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Khoronenkova, Svetlana V. Dianov, Grigory L. |
| Description | Author Affiliation: Khoronenkova SV ( Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom); Dianov GL ( Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom); |
| Abstract | DNA single-strand breaks (SSBs) arise as a consequence of spontaneous DNA instability and are also formed as DNA repair intermediates. Their repair is critical because they otherwise terminate gene transcription and generate toxic DNA double-strand breaks (DSBs) on replication. To prevent the formation of DSBs, SSB repair must be completed before DNA replication. To accomplish this, cells should be able to detect unrepaired SSBs, and then delay cell cycle progression to allow more time for repair; however, to date there is no evidence supporting the coordination of SSB repair and replication in human cells. Here we report that ataxia-telangiectasia mutated kinase (ATM) plays a major role in restricting the replication of SSB-containing DNA and thus prevents DSB formation. We show that ATM is activated by SSBs and coordinates their repair with DNA replication. SSB-mediated ATM activation is followed by a G1 cell cycle delay that allows more time for repair and thus prevents the replication of damaged DNA and DSB accrual. These findings establish an unanticipated role for ATM in the signaling of DNA SSBs and provide important insight into the molecular defects leading to genetic instability in patients with ataxia-telangiectasia. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 13 |
| Volume Number | 112 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2015-04-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Ataxia Telangiectasia Mutated Proteins Metabolism Cell Cycle DNA Breaks, Double-Stranded DNA Breaks, Single-Stranded DNA Repair Apoptosis Cell Line Comet Assay DNA Chemistry DNA-Binding Proteins Fibroblasts Gene Silencing Genome Microscopy, Fluorescence Mutation Phosphorylation RNA, Small Interfering Signal Transduction Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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