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

• Published in: Molecular cell 2015-11, Vol.60 (3), p.351-361
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; DNA Damage; DNA Helicases - genetics; DNA Helicases - metabolism; DNA Replication; Fanconi Anemia Complementation Group Proteins - genetics; Fanconi Anemia Complementation Group Proteins - metabolism; Genomic Instability; HeLa Cells; Humans; Leukemia - genetics; Leukemia - metabolism; Leukemia - pathology; Mice; Mice, Knockout; Mutation; Nucleic Acid Heteroduplexes - genetics; Nucleic Acid Heteroduplexes - metabolism
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2015.09.012

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. [Display omitted] •Replication and transcription collisions cause genome instability in FA•A functional FA pathway protects cells from unscheduled accumulation of R-loops•Transcription inhibition or R-loop removal restores normal replication in FA cells•FANCM resolves R-loops via its translocase activity Schwab et al. show that the FA pathway prevents DNA lesions caused by conflicts between replication and transcription and by transcription-associated DNA:RNA hybrids (R-loops). FA proteins can stabilize stalled replication forks, and FANCM resolves R-loops via its translocase activity.