R-loop proximity proteomics identifies a role of DDX41 in transcription-associated genomic instability

Thorsten Mosler, Francesca Conte, Gabriel M. C. Longo, Ivan Mikicic, Nastasja Kreim, Martin M. Möckel, Giuseppe Petrosino, Johanna Flach, Joan Barau, Brian Luke, Vassilis Roukos and Petra Beli ()
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Thorsten Mosler: Institute of Molecular Biology (IMB)
Francesca Conte: Institute of Molecular Biology (IMB)
Gabriel M. C. Longo: Institute of Molecular Biology (IMB)
Ivan Mikicic: Institute of Molecular Biology (IMB)
Nastasja Kreim: Institute of Molecular Biology (IMB)
Martin M. Möckel: Institute of Molecular Biology (IMB)
Giuseppe Petrosino: Institute of Molecular Biology (IMB)
Johanna Flach: Medical Faculty Mannheim of the Heidelberg University
Joan Barau: Institute of Molecular Biology (IMB)
Brian Luke: Institute of Molecular Biology (IMB)
Vassilis Roukos: Institute of Molecular Biology (IMB)
Petra Beli: Institute of Molecular Biology (IMB)

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Transcription poses a threat to genomic stability through the formation of R-loops that can obstruct progression of replication forks. R-loops are three-stranded nucleic acid structures formed by an RNA–DNA hybrid with a displaced non-template DNA strand. We developed RNA–DNA Proximity Proteomics to map the R-loop proximal proteome of human cells using quantitative mass spectrometry. We implicate different cellular proteins in R-loop regulation and identify a role of the tumor suppressor DDX41 in opposing R-loop and double strand DNA break accumulation in promoters. DDX41 is enriched in promoter regions in vivo, and can unwind RNA–DNA hybrids in vitro. R-loop accumulation upon loss of DDX41 is accompanied with replication stress, an increase in the formation of double strand DNA breaks and transcriptome changes associated with the inflammatory response. Germline loss-of-function mutations in DDX41 lead to predisposition to acute myeloid leukemia in adulthood. We propose that R-loop accumulation and genomic instability-associated inflammatory response may contribute to the development of familial AML with mutated DDX41.

Date: 2021
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DOI: 10.1038/s41467-021-27530-y

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