The Fanconi Anemia Pathway Maintains Genome Stability by Coordinating Replication and Transcription
| Autor: | Chih-Chao Liang, Jamie Langton, Andrew J. Deans, Fenil Shah, Richard J. Gibbons, Martin A. Cohn, Jadwiga Nieminuszczy, Wojciech Niedzwiedz, Rebekka A. Schwab, David Lopez Martinez |
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| Rok vydání: | 2015 |
| Předmět: |
DNA Replication
Eukaryotic DNA replication Genomic Instability DNA replication factor CDT1 Mice Replication factor C Control of chromosome duplication Animals Humans FANCM Molecular Biology Genetics Mice Knockout Leukemia biology DNA replication DNA Helicases Nucleic Acid Heteroduplexes Cell Biology Fanconi Anemia Complementation Group Proteins Replication fork arrest Mutation biology.protein Origin recognition complex DNA Damage HeLa Cells |
| Zdroj: | Molecular cell. 60(3) |
| ISSN: | 1097-4164 |
| Popis: | DNA replication stress can cause chromosomal instability and tumor progression. One key pathway that counteracts replication stress and promotes faithful DNA replication consists of the Fanconi anemia (FA) proteins. However, how these proteins limit replication stress remains largely elusive. Here we show that conflicts between replication and transcription activate the FA pathway. Inhibition of transcription or enzymatic degradation of transcription-associated R-loops (DNA:RNA hybrids) suppresses replication fork arrest and DNA damage occurring in the absence of a functional FA pathway. Furthermore, we show that simple aldehydes, known to cause leukemia in FA-deficient mice, induce DNA:RNA hybrids in FA-depleted cells. Finally, we demonstrate that the molecular mechanism by which the FA pathway limits R-loop accumulation requires FANCM translocase activity. Failure to activate a response to physiologically occurring DNA:RNA hybrids may critically contribute to the heightened cancer predisposition and bone marrow failure of individuals with mutated FA proteins. |
| Databáze: | OpenAIRE |
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