As a genome guardian,p53 maintains genome stability by arresting cells for damage repair or inducing cell apoptosis to eliminate the damaged cells in stress response.Several nucleolar proteins stabilize p53 by interfering Mdm2-p53 interaction upon cellular stress,while other mechanisms by which nucleolar proteins activate p53 remain to be determined.Here,we identify NAT10 as a novel regulator for p53 activation.NAT10 acetylates p53 at K120 and stabilizes p53 by counteracting Mdm2 action.In addition,NAT10 promotes Mdm2 degradation with its intrinsic E3 ligase activity.After DNA damage,NAT10 translocates to nucleoplasm and activates p53-mediated cell cycle control and apoptosis.Finally,NAT10 inhibits cell proliferation and expression of NAT10 decreases in human colorectal carcinomas.Thus,our data demonstrate that NAT10 plays a critical role in p53 activation via acetylating p53 and counteracting Mdm2 action,providing a novel pathway by which nucleolar protein activates p53 as a cellular stress sensor.