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DNA damage triggers SAF-A and RNA biogenesis factors exclusion from chromatin coupled to R-loops removal

Abstract : We previously identified the heterogeneous ribonucleoprotein SAF-A/hnRNP U as a substrate for DNAPK, a protein kinase involved in DNA damage response (DDR). Using laser micro-irradiation in human cells, we report here that SAF-A exhibits a twophase dynamics at sites of DNA damage, with a rapid and transient recruitment followed by a prolonged exclusion. SAF-A recruitment corresponds to its binding to Poly(ADP-ribose) while its exclusion is dependent on the activity of ATM, ATR and DNAPK and reflects the dissociation from chromatin of SAF-A associated with ongoing transcription. Having established that SAF-A RNA-binding domain recapitulates SAF-A dynamics, we show that this domain is part of a complex comprising several mRNA biogenesis proteins of which at least two, FUS/TLS and TAFII68/TAF15, exhibit similar biphasic dynamics at sites of damage. Using an original reporter for live imaging of DNA:RNA hybrids (R-loops), we show a transient transcription-dependent accumulation of R-loops at sites of DNA damage that is prolonged upon inhibition of RNA biogenesis factors exclusion. We propose that a new component of the DDR is an active anti-R-loop mechanism operating at damaged transcribed sites which includes the exclusion of mRNA biogenesis factors such as SAF-A, FUS and TAF15.
Keywords : DNA RNA R-loops
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Sébastien Britton, Emma Dernoncourt, Christine Delteil, Carine Froment, Odile Schiltz, et al.. DNA damage triggers SAF-A and RNA biogenesis factors exclusion from chromatin coupled to R-loops removal. Nucleic Acids Research, Oxford University Press, 2014, 42 (14), pp.9047-9062. ⟨10.1093/nar/gku601⟩. ⟨hal-01191434⟩

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