Cargando…
The Fanconi Anemia Pathway Maintains Genome Stability by Coordinating Replication and Transcription
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 w...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4644232/ https://www.ncbi.nlm.nih.gov/pubmed/26593718 http://dx.doi.org/10.1016/j.molcel.2015.09.012 |
_version_ | 1782400637269442560 |
---|---|
author | Schwab, Rebekka A. Nieminuszczy, Jadwiga Shah, Fenil Langton, Jamie Lopez Martinez, David Liang, Chih-Chao Cohn, Martin A. Gibbons, Richard J. Deans, Andrew J. Niedzwiedz, Wojciech |
author_facet | Schwab, Rebekka A. Nieminuszczy, Jadwiga Shah, Fenil Langton, Jamie Lopez Martinez, David Liang, Chih-Chao Cohn, Martin A. Gibbons, Richard J. Deans, Andrew J. Niedzwiedz, Wojciech |
author_sort | Schwab, Rebekka A. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4644232 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-46442322015-12-08 The Fanconi Anemia Pathway Maintains Genome Stability by Coordinating Replication and Transcription Schwab, Rebekka A. Nieminuszczy, Jadwiga Shah, Fenil Langton, Jamie Lopez Martinez, David Liang, Chih-Chao Cohn, Martin A. Gibbons, Richard J. Deans, Andrew J. Niedzwiedz, Wojciech Mol Cell Article 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. Cell Press 2015-11-05 /pmc/articles/PMC4644232/ /pubmed/26593718 http://dx.doi.org/10.1016/j.molcel.2015.09.012 Text en Crown Copyright © 2015 Published by Elsevier Inc. All rights reserved. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Schwab, Rebekka A. Nieminuszczy, Jadwiga Shah, Fenil Langton, Jamie Lopez Martinez, David Liang, Chih-Chao Cohn, Martin A. Gibbons, Richard J. Deans, Andrew J. Niedzwiedz, Wojciech The Fanconi Anemia Pathway Maintains Genome Stability by Coordinating Replication and Transcription |
title | The Fanconi Anemia Pathway Maintains Genome Stability by Coordinating Replication and Transcription |
title_full | The Fanconi Anemia Pathway Maintains Genome Stability by Coordinating Replication and Transcription |
title_fullStr | The Fanconi Anemia Pathway Maintains Genome Stability by Coordinating Replication and Transcription |
title_full_unstemmed | The Fanconi Anemia Pathway Maintains Genome Stability by Coordinating Replication and Transcription |
title_short | The Fanconi Anemia Pathway Maintains Genome Stability by Coordinating Replication and Transcription |
title_sort | fanconi anemia pathway maintains genome stability by coordinating replication and transcription |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4644232/ https://www.ncbi.nlm.nih.gov/pubmed/26593718 http://dx.doi.org/10.1016/j.molcel.2015.09.012 |
work_keys_str_mv | AT schwabrebekkaa thefanconianemiapathwaymaintainsgenomestabilitybycoordinatingreplicationandtranscription AT nieminuszczyjadwiga thefanconianemiapathwaymaintainsgenomestabilitybycoordinatingreplicationandtranscription AT shahfenil thefanconianemiapathwaymaintainsgenomestabilitybycoordinatingreplicationandtranscription AT langtonjamie thefanconianemiapathwaymaintainsgenomestabilitybycoordinatingreplicationandtranscription AT lopezmartinezdavid thefanconianemiapathwaymaintainsgenomestabilitybycoordinatingreplicationandtranscription AT liangchihchao thefanconianemiapathwaymaintainsgenomestabilitybycoordinatingreplicationandtranscription AT cohnmartina thefanconianemiapathwaymaintainsgenomestabilitybycoordinatingreplicationandtranscription AT gibbonsrichardj thefanconianemiapathwaymaintainsgenomestabilitybycoordinatingreplicationandtranscription AT deansandrewj thefanconianemiapathwaymaintainsgenomestabilitybycoordinatingreplicationandtranscription AT niedzwiedzwojciech thefanconianemiapathwaymaintainsgenomestabilitybycoordinatingreplicationandtranscription AT schwabrebekkaa fanconianemiapathwaymaintainsgenomestabilitybycoordinatingreplicationandtranscription AT nieminuszczyjadwiga fanconianemiapathwaymaintainsgenomestabilitybycoordinatingreplicationandtranscription AT shahfenil fanconianemiapathwaymaintainsgenomestabilitybycoordinatingreplicationandtranscription AT langtonjamie fanconianemiapathwaymaintainsgenomestabilitybycoordinatingreplicationandtranscription AT lopezmartinezdavid fanconianemiapathwaymaintainsgenomestabilitybycoordinatingreplicationandtranscription AT liangchihchao fanconianemiapathwaymaintainsgenomestabilitybycoordinatingreplicationandtranscription AT cohnmartina fanconianemiapathwaymaintainsgenomestabilitybycoordinatingreplicationandtranscription AT gibbonsrichardj fanconianemiapathwaymaintainsgenomestabilitybycoordinatingreplicationandtranscription AT deansandrewj fanconianemiapathwaymaintainsgenomestabilitybycoordinatingreplicationandtranscription AT niedzwiedzwojciech fanconianemiapathwaymaintainsgenomestabilitybycoordinatingreplicationandtranscription |