Fig. 3

HUWE1-mediated apoptosis. a Upon TNFα stimulation, HUWE1 can mediate K48-linked polyubiquitination of Miz-1, thereby facilitating the degradation of Miz-1 protein. Miz-1 suppresses TNFα-induced JNK activation and cell death. Reduced Miz-1 levels relieve this negative regulation on TNFα. b When DNA damage occurs, cells undergo cell-cycle arrest and apoptosis by enhancing the activities of p53, downregulating the expressions of anti-apoptotic molecules (i.e. Mcl-1) and the assembly of pre-replicative complex (Cdc6 in preRC). HUWE1 is an associating protein of the tumor suppressor, ARF, which plays a pivotal role in regulating p53 and inhibits the ubiquitin ligase activity of HUWE1. Expression of HUWE1 can directly ubiquitinate and degrade p53 in a Mdm2-independent way, thereby suppressing p53-dependent apoptosis. HUWE1 mediates polyubiquitination of HDAC2, which deacetylates p53 and affects p53 transcriptional activity. HUWE1 deficiency leads to accumulation of HDAC2 and compromised p53 acetylation and apoptotic response upon DNA damage. HUWE1 interacts with Mcl-1 through the BH3 domain, causing Mcl-1 degradation upon DNA damage. Cdc6 plays a key role in DNA replication and degradation of Cdc6 mediated by HUWE1 polyubiquitination occurs upon ultraviolet irradiation or DNA alkylation, resulting in cell-cycle arrest and apoptosis