E3 ubiquitin-protein ligase RNF168 (RNF168)

E3 ubiquitin-protein ligase RNF168 (RNF168) is a chromatin-associated, RING-type E3 ubiquitin ligase essential for the cellular response to DNA double-strand breaks (DSBs)[2][5]. RNF168 is recruited to chromatin at DNA damage sites, where it amplifies ubiquitination of histone H2A and H2AX at lysine 13 and 15, working downstream of RNF8 and in concert with the E2 enzyme UBE2N/UBC13[2][3][4][5]. This ubiquitin signaling cascade is necessary to achieve a threshold density of modified histones, enabling efficient recruitment of repair factors such as 53BP1 and BRCA1 to DSBs, thus promoting genome stability and DNA repair by non-homologous end-joining (NHEJ) and homologous recombination pathways[1][2][3][4][8]. RNF168 also plays roles in transcriptional silencing near DNA lesions, class switch recombination in B cells, and interstrand cross-link (ICL) repair[2][3]. Mutations or dysregulation of RNF168 are linked to cancer susceptibility and rare genetic syndromes such as RIDDLE syndrome, due to impaired DNA repair and genome maintenance. No approved drugs directly target RNF168, but it constitutes a mechanistically defined, disease-relevant molecular target within the DNA damage response and repair machinery.

Other names

RING finger protein 168RING-type E3 ubiquitin transferase RNF168hRNF168FLJ35794RIDLE3 ubiquitin-protein ligase RNF168ring finger protein 168E3 ubiquitin protein ligase

Drugs would theoretically function by modulating E3 ubiquitin ligase activity, either inhibiting RNF168-mediated histone ubiquitination or interfering with its recruitment to DNA lesions[2][5]. No clinically validated inhibitors are available.