RNF146

RNF146 is a human gene encoding a RING finger E3 ubiquitin ligase. The protein, also known as Iduna, contains a WWE domain that binds poly(ADP-ribose) (PAR) chains generated by PARP enzymes at sites of DNA damage, and a C-terminal RING finger domain that mediates ubiquitination. This combination enables RNF146 to recognize PARylated substrates and tag them with ubiquitin for proteasomal degradation.

Functionally, RNF146 operates as a PAR-dependent ubiquitin ligase, linking PAR signaling to the ubiquitin–proteasome system. By ubiquitinating PARylated proteins, it facilitates their turnover and helps regulate protein levels after DNA damage and during DNA damage response pathways. This mechanism contributes to maintaining cellular proteostasis in stressed cells.

Biological roles attributed to RNF146/Iduna include participation in the cellular response to genotoxic stress and modulation of PARP1-related signaling. In neuronal models, Iduna has been described as neuroprotective under ischemic and oxidative stress conditions, with proposed mechanisms involving attenuation of PAR-mediated cell death pathways, though the precise substrates and in vivo significance remain areas of active research.

RNF146 is conserved across vertebrates and is broadly expressed, supporting a general role in DNA damage response and proteostasis. In cancer biology, dysregulation of RNF146 activity has been explored for its potential impact on cellular responses to DNA-damaging treatments and PARP inhibitors, making RNF146 a subject of interest for therapeutic strategies.