Survival of the Replication Checkpoint Deficient Cells Requires MUS81-RAD52 Function

In checkpoint-deficient cells,dna double-strand breaks (dsbs) are produced during replication by the structure-specific endonuclease mus81. the mechanism underlying mus81-dependent cleavage,and the effect on chromosome integrity and viability of checkpoint deficient cells is only partly understood,especially in human cells. here,we show that mus81-induced dsbs are specifically triggered by chk1 inhibition in a manner that is unrelated to the loss of rad51,and does not involve formation of a rad51 substrate. indeed,chk1 deficiency results in the formation of a rad52-dependent structure that is cleaved by mus81. moreover,in chk1-deficient cells depletion of rad52,but not of mus81,rescues chromosome instability observed after replication fork stalling. however,when rad52 is down-regulated,recovery from replication stress requires mus81,and loss of both these proteins results in massive cell death that can be suppressed by rad51 depletion. our findings reveal a novel rad52/mus81-dependent mechanism that promotes cell viability and genome integrity in checkpoint-deficient cells,and disclose the involvement of mus81 to multiple processes after replication stress. © 2013 murfuni et al.