Figure 3.

Mus81 regulation by replication checkpoint. In yeast, replication stress induces Rad3^S.p./Mec1^S.c. (ATR in human) activation of Cds1^S.p./Rad53^S.c. by promoting its association with Mrc1^S.p./S.c. (CLASPIN in human) (reviewed in [80]). Upon acute and severe replication stress such as hydroxyurea treatment, Cds1^S.p. limits Mus81^S.p. activity (indicated by solid red line) [44]. Cds1^S.p. inhibits Rad60^S.p. activity (indicated by blue line) by promoting delocalization from the nucleus [82,83]. Mrc1^S.p./S.c. protein level regulates recruitment of Rqh1^S.p. homolog Sgs1^S.c. to chromatin (indicated by blue arrow) [74]. Both Rad60^S.p./Esc2^S.c. and Rqh1^S.p./Sgs1^S.c. contribute to Mus81 activity (indicated by dashed blue arrow) [75,76]. In human cells, DNA damage checkpoint CHK1 and Cds1-homolog CHK2 is activated downstream of ATM/ATR kinases (reviewed in [79,80]) [77]. It is unclear whether MUS81 is directly regulated by these checkpoint kinases in human cells. However, there is evidence that CHK2 upregulates MUS81 protein levels and MUS81 in turn contributes to CHK2 activation upon DNA damage (indicated by dashed double-headed arrow) [84]. Deleterious MUS81-dependent processing of replication intermediates following CHK1 inhibition suggests that CHK1 downregulates MUS81 activity (indicated by dashed red line) [68,69,70].