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Review
. 2022 May;289(9):2467-2480.
doi: 10.1111/febs.15857. Epub 2021 Apr 16.

New answers to the old RIDDLE: RNF168 and the DNA damage response pathway

Jessica Kelliher  1 , Gargi Ghosal  2 , Justin Wai Chung Leung  1
Affiliations
Review

New answers to the old RIDDLE: RNF168 and the DNA damage response pathway

Jessica Kelliher et al. FEBS J. 2022 May.

Abstract

The chromatin-based DNA damage response pathway is tightly orchestrated by histone post-translational modifications, including histone H2A ubiquitination. Ubiquitination plays an integral role in regulating cellular processes including DNA damage signaling and repair. The ubiquitin E3 ligase RNF168 is essential in assembling a cohort of DNA repair proteins at the damaged chromatin via its enzymatic activity. RNF168 ubiquitinates histone H2A(X) at the N terminus and generates a specific docking scaffold for ubiquitin-binding motif-containing proteins. The regulation of RNF168 at damaged chromatin and the mechanistic implication in the recruitment of DNA repair proteins to the damaged sites remain an area of active investigation. Here, we review the function and regulation of RNF168 in the context of ubiquitin-mediated DNA damage signaling and repair. We will also discuss the unanswered questions that require further investigation and how understanding RNF168 targeting specificity could benefit the therapeutic development for cancer treatment.

Keywords: DNA double-strand break; DNA repair; RIDDLE syndrome; RIDDLIN; ubiquitin.

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Conflict of interest statement

Conflicts of Interest

The authors declare no conflict of interest

Figures

Figure 1.
Figure 1.. Human RNF168 (RIDDLIN), an evolutionarily conserved ubiquitin E3 ligase
RNF168 is composed of a catalytic RING domain and two ubiquitin-dependent DSB recruitment modules (UDM). UDM1 is composed by LRM, UMI and MIU1 and UDM2 is composed by UAD, MIU2 and LRM. RNF168 also contains an arginine anchor for substrate recognition. Corresponding conservation score was analyzed using the ConSurf Server: https://consurf.tau.ac.il. Conservation score is calculated using an empirical Bayesian methodology by comparing 107 vertebrates that share 35–95% homology. The scores are normalized and grouped into nine conservation grades [23]. Mutations found in patients with RIDDLE syndrome are marked on the schematic illustration of RNF168 as E99Kfs*, R131X, A133Gfs* and N441Rfs*. LRM (LR motif); UMI (UIM: ubiquitin interacting motif- and MIU: motif interacting with ubiquitin-related ubiquitin-binding motif) and MIU (Motif interacting with ubiquitin); UAD (ubiquitin associated domain); PID (PALB2 interacting domain).
Figure 2.
Figure 2.. Conservation of the RNF168 functional domains
Evolutionary conservation scores were analyzed by the ConSurf Server and pseudo-colored to indicate amino acid conservation. A) Ribbon (left) and space-filling (right) models of the RNF168 RING domain crystal structure (PDB ID:4GB0). B) Ribbon (Top) and space-filling (bottom) of the RNF168 UBD1 (PDB ID:5XIS) crystal structure. C) Ribbon (Top) and space-filling (bottom) of the RNF168 UDM2 (PDB ID: 5XIU) crystal structure. Labeled sticks indicate the characterized functional residues.
Figure 3.
Figure 3.. RNF168 as a key DNA repair molecular switch on damaged chromatin
A) A simplified overview of the genetic regulation of RNF168 accrual at damaged chromatin. B) The RNF168-mediated H2A(X) K15 ubiquitination and the characterized potential readers that are involved in DNA repair. C) The unsolved riddle of RNF168. Schematic representation of the uncharacterized RNF168 substrates H2AZ and macroH2A and the unidentified RNF168 substrate that regulates RAP80 and BRCA1 IRIF.
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