RNF138

RNF138 Full Name

ring finger protein 138, E3 ubiquitin protein ligase

RNF138 Introduction

RNF138 (ring finger protein 138) is an E3 ubiquitin ligase whose activity has been most clearly linked to the cellular response to DNA damage and to the control of signaling pathways that depend on regulated protein destruction. The protein combines a RING finger with ubiquitin-binding motifs, an architecture that allows it both to conjugate ubiquitin onto substrates and to recognize ubiquitinated partners, positioning RNF138 at the hub of ubiquitin-dependent decision making in the cell. In the DNA damage response, RNF138 is recruited to sites of double-strand breaks, where it ubiquitinates repair factors and promotes the resection of broken DNA ends that is required for homologous recombination, an error-free pathway of DNA repair. Loss or inhibition of RNF138 therefore sensitizes cells to ionizing radiation and to chemotherapeutic agents that generate double-strand breaks, a property with obvious implications for cancer treatment. The ligase has also been connected to Wnt signaling and to the regulation of protein turnover in other contexts, suggesting that it coordinates genome maintenance with cell fate decisions. Its multifaceted roles make RNF138 a compelling subject for studies of how ubiquitination safeguards genome integrity.

Figure 1. RNF138:ring finger protein 138,e3 ubiquitin ligase.

RING Finger, Ubiquitin-Binding Modules, and Recruitment to DNA Breaks
The N-terminal RING domain of RNF138 confers E3 ligase activity, enabling the transfer of ubiquitin from an E2 enzyme onto lysine residues of substrate proteins.
Additional ubiquitin-interacting motifs allow RNF138 to recognize pre-existing ubiquitin chains, an important feature for a protein that operates within the densely ubiquitinated environment of damaged chromatin.
In response to DNA double-strand breaks, RNF138 is rapidly recruited to the damaged site, where it collaborates with the ubiquitin machinery that assembles around the break.
Biochemical studies indicate that RNF138 ubiquitinates proteins involved in the early steps of the DNA damage response, thereby promoting the resection of DNA ends that generates single-stranded DNA for homologous recombination.
The RNF138 gene is situated on human chromosome 18, and the protein is broadly expressed, consistent with a housekeeping role in genome maintenance.
Its activity is regulated by the DNA damage signaling network, and the ligase shows dynamic accumulation and dispersal at repair foci as the damage response proceeds.
This combination of catalytic and ubiquitin-sensing functions allows RNF138 to act both as an enzyme and as an adaptor within the repair machinery.

Homologous Recombination, Genome Stability, and Therapeutic Targeting
Homologous recombination repairs DNA double-strand breaks with high fidelity by using the sister chromatid as a template, and the DNA-end resection promoted by RNF138 is an obligatory first step of this pathway.
Cells depleted of RNF138 display reduced homologous recombination efficiency, accumulation of unrepaired breaks, and hypersensitivity to ionizing radiation and to drugs such as PARP inhibitors and certain chemotherapeutics.
This phenotype places RNF138 among the growing list of DNA repair factors whose inhibition could be exploited to kill cancer cells that already harbor repair defects, an approach known as synthetic lethality.
Beyond DNA repair, RNF138 has been reported to influence Wnt/beta-catenin signaling and other pathways by controlling the stability of key regulatory proteins, indicating that its functions extend to cell fate and development.
Because RNF138 acts early in the repair reaction, it represents an attractive point of intervention: inhibiting the ligase would disable homologous recombination while leaving other repair processes largely intact.
Development of selective RNF138 inhibitors is at an early stage, and a deeper understanding of its substrate repertoire will be required to predict which tumor types would benefit most from such therapy.

Alternate Names for RNF138

RNF138; ring finger protein 138, E3 ubiquitin protein ligase; ring finger protein 138; E3 ubiquitin-protein ligase RNF138; STRIN; NLK-associated RING finger protein; Nemo-like kinase-associated RING finger protein; NARF; HSD-4; hNARF; MGC8758;