Chromatin relaxation triggers induction of cell cycle inhibitor p19INK4d regardless of dna damage

SIRKIN P.F.; OGARA M.F.; GIONO L.E.; CÁNEPA, E.T.

Puerto Madryn

Congreso; XLVI REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN EN BIOQUÍMICA Y BIOLOGÍA MOLECULAR (SAIB); 2010

SOCIEDAD ARGENTINA DE INVESTIGACIÓN EN BIOQUÍMICA Y BIOLOGÍA MOLECULAR (SAIB)

It is widely reported that chromatin suffers rearrangements whenDNA damage is generated. However, the role of chromatin in theDNA damage response of a cell is not yet well understood.p19INK4d, a member of the INK4 cell cycle inhibitors, is inducedafter endogenous DNA damage. However, when exogenously DNAdamaged molecules are introduced into the cell, this induction is notobserved, suggesting that the actual trigger of p19 induction shouldbe something else other than DNA damage itself. Here we show thatthree different chromatin relaxing agents (chloroquine, trichostatinand hypotonic medium) trigger transcriptional induction of p19, andthat this happens even in the absence of DNA damage. Interestingly,this induction was shown to depend upon ATM, Chk1 and Chk2kinase activity, as is the case for endogenous DNA damage p19induction. In addition, the induction of p19 elicited by chromatinrelaxation is also mediated by the transcription factor E2F1.Notably, when cells were exposed to both situations simultaneously,no increase in p19 mRNA levels was observed with respect to thelevels obtained with one condition alone, suggesting that DNAdamage and chromatin relaxation share the signaling pathway. Thespecific induction of p19 by chromatin structure alterationssupports a role for p19 as a sensor of DNA damage