Journal article

The Fanconi Anemia Pathway Maintains Genome Stability by Coordinating Replication and Transcription

Rebekka A Schwab, Jadwiga Nieminuszczy, Fenil Shah, Jamie Langton, David Lopez Martinez, Chih-Chao Liang, Martin A Cohn, Richard J Gibbons, Andrew J Deans, Wojciech Niedzwiedz

Molecular Cell | CELL PRESS | Published : 2015

Abstract

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 ..

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Grants

Awarded by Royal Society


Awarded by Medical Research Council


Awarded by Worldwide Cancer Research


Funding Acknowledgements

We thank Profs. K.J. Patel and M. Takata and Dr. G. Stewart for cell lines and Profs. A. Harris, K.J. Patel, P. McHugh, and N.J. Proudfoot for plasmids, antibodies, and siRNA. We thank Dr. D. Waithe (Wolfson Imaging Centre, Oxford) for his help with analysis of fluorescence immunostainings. We also thank Profs. K.J. Patel and J. Walter for helpful comments on the manuscript. This work was funded by a Worldwide Cancer Research International Fellowship and a WIMM/Medical Research Council Senior Non-Clinical Fellowship (to W.N.), Royal Society Grant UF100717 (to M.A.C.), a Goodger scholarship (to C.C.L.), and MRC and Clarendon scholarships (to D.L.M.). R.J.G's research is supported by the Medical Research Council (grant H4R00121-H40D) A. J. D. is a National Breast Cancer Foundation fellow supported by funding from NHMRC, the Fanconi Anemia Research Fund, and the Victorian Government IOS program.