Amir Hay - DNA-PK impedes DNA demage-induced transcription of stress response genes
Channel: Institut des Hautes Études Scientifiques (IHÉS)
Date: 27/03/2018

Organisms are continuously exposed to sublethal stresses, but how they respond to such stresses at the molecular level is still largely unknown. One known mechanism is genetic regulation  of  stress  response  proteins,  such  as  HSP72 -which  is  encoded  by  both HSPA1A  and  HSPA1B  genes.  We  previously  reported  that  HIRA,  a  histone  H3 chaperone, is prompted by sublethal stresses to establish acquired tolerance to subsequent lethal
stresses  in  both S.  pombeand  human  fibroblasts.  This suggested  that  chromatin remodeling  plays  a  role  in  sublethal  stress  response.  Here,  we  determined  that  DNA damage response (DDR) factors and topoisomerases are potent histone H3 interactors and identifed  their  role  in  the  regulation  of  stress  response  in  human  fibroblasts.  Our  results indicate   that   sublethal   stress   induces   DNA   double-stranded   breaks   (DSBs)   by topoisomerase  IIA  (TOP2A).  Moreover,  we  show  that  following  sublethal  heat  stress, histone variant H3.3 and its interactors, including DDR factors and TOP2A, are enriched 
at the transcription start site and/or open reading frame of the HSPA1A/B loci. Lastly, we determined that DDR protein DNA-PK is a negative regulator of HSPA1A/B expression following DSB-induced transcription. Based on our results we propose that in response to sublethal  stresses,  HIRA/H3.3  and  DNA-PK  counter-regulate  stress  response  genes  to balance transcription  and  DNA  damage  response,  for  immediate  survival  and  genomic stability, respectively.