DNA damage triggers SAF-A and RNA biogenesis factors exclusion from chromatin coupled to R-loops removal
Résumé
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.
Domaines
Sciences du Vivant [q-bio]
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