The SWR1 complex replaces the canonical histone H2A with the variant H2A.Z (Htz1 
in yeast) at specific chromatin regions. This dynamic alteration in nucleosome 
structure provides a molecular mechanism to regulate transcription, gene 
silencing, chromosome segregation and DNA repair. Here we show that genetic 
instability, sensitivity to drugs impairing different cellular processes and 
genome-wide transcriptional misregulation in htz1Delta can be partially or 
totally suppressed if SWR1 is not formed (swr1Delta), if it forms but cannot 
bind to chromatin (swc2Delta) or if it binds to chromatin but lacks histone 
replacement activity (swc5Delta and the ATPase-dead swr1-K727G). These results 
suggest that in htz1Delta the nucleosome remodelling activity of SWR1 affects 
chromatin integrity because of an attempt to replace H2A with Htz1 in the 
absence of the latter. This would impair transcription and, either directly or 
indirectly, other cellular processes. Specifically, we show that in htz1Delta, 
the SWR1 complex causes an accumulation of recombinogenic DNA damage by a 
mechanism dependent on phosphorylation of H2A at Ser129, a modification that 
occurs in response to DNA damage, suggesting that the SWR1 complex impairs the 
repair of spontaneous DNA damage in htz1Delta. In addition, SWR1 causes DSBs 
sensitivity in htz1Delta; consistently, in the absence of Htz1 the SWR1 complex 
bound near an endonuclease HO-induced DSB at the mating-type (MAT) locus impairs 
DSB-induced checkpoint activation. Our results support a stepwise mechanism for 
the replacement of H2A with Htz1 and demonstrate that a tight control of this 
mechanism is essential to regulate chromatin dynamics but also to prevent the 
deleterious consequences of an incomplete nucleosome remodelling.