Figure 9. A schematic diagram depicting a model for RNF8-mediated coregulation of Notch signaling and DSB repair and the breast cancer–suppressive function of RNF8.

RNF8 is recruited to DSBs, where it ubiquitylates histones at the flanking DNA damage sites. This ubiquitylation triggers recruitment of downstream DSB signaling and repair proteins (e.g., RNF168 and BRCA1) to DNA damage sites, allowing their repair. Loss of RNF8 expression or function impairs DSB repair, leading to genomic instability and increased breast cancer risk. Our data reveal an important role for RNF8 in mediating negative regulation of Notch signaling. RNF8 ubiquitylates the active form of NOTCH1 (N1ICD) to promote its turnover. Thus, impaired RNF8 expression or function results in constitutive activation of Notch signaling in mammary luminal progenitors, a process that promotes expansion of these progenitors and increases their risk for malignant transformation. We propose that RNF8 coregulation of Notch signaling and DSB repair is critical for its suppressor function in breast cancer. Small filled circles indicate γH2ax (black); phosphorylation (gray); and Ub (red).