Fig. 4

HUWE1-mediated DNA repair. HUWE1 mediates H2AX and BRCA1 ubiquitination and degradation. Upon double-strand breaks (DSB), two major DNA repair systems are activated: homologous recombination (HR) and non-homologous end joining (NHEJ). Phosphorylation of H2AX (γH2AX) initiates a DNA damage signaling cascade and has been implicated in both DSB repair systems. BRCA1 is a pleiotropic DNA damage response protein and mainly plays a significant role in HR. HUWE1 also participates in base excision repair by regulating the protein turnover of Pol β, and Pol λ. HUWE1 catalyzes mono-ubiquitination of Pol β at Lys-41, 61, and 81 and of Pol λ at Lys-27 (major site) and Lys-273. Mono-ubiquitinated Pol β is later poly-ubiquitinated by another E3 ligase, CHIP, for protein degradation. Pol λ mono-ubiquitination, on the other hand, is regulated by Cdk2/cyclinA-mediated phosphorylation. As ARF negatively regulates the HUWE1 activity, knockdown of ARF decreases the protein levels of Pol β and Pol λ