DNA damage triggers SAF-A and RNA biogenesisfactors exclusion from chromatin coupled to R-loopsremoval
2014
Dernoncourt, Emma | Delteil, Christine | Froment, Carine | Schiltz, Odile | Salles, Bernard | Frit, Philippe
We previously identified the heterogeneous ribonucleoproteinSAF-A/hnRNP U as a substrate for DNAPK,a protein kinase involved in DNA damage response(DDR). Using laser micro-irradiation in humancells, we report here that SAF-A exhibits a twophasedynamics at sites of DNA damage, with arapid and transient recruitment followed by a prolongedexclusion. SAF-A recruitment corresponds toits binding to Poly(ADP-ribose) while its exclusionis dependent on the activity of ATM, ATR and DNAPKand reflects the dissociation from chromatin ofSAF-A associated with ongoing transcription. Havingestablished that SAF-A RNA-binding domain recapitulatesSAF-A dynamics, we show that this domainis part of a complex comprising several mRNAbiogenesis proteins of which at least two, FUS/TLSand TAFII68/TAF15, exhibit similar biphasic dynamicsat sites of damage. Using an original reporter forlive imaging of DNA:RNA hybrids (R-loops), we showa transient transcription-dependent accumulation ofR-loops at sites of DNA damage that is prolongedupon inhibition of RNA biogenesis factors exclusion.We propose that a new component of the DDR isan active anti-R-loop mechanism operating at damagedtranscribed sites which includes the exclusionof mRNA biogenesis factors such as SAF-A, FUS andTAF15.
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