An E2-guided E3 Screen Identifies the RNF17-UBE2U Pair as Regulator of the Radiosensitivity, Immunodeficiency, Dysmorphic Features, and Learning Difficulties (RIDDLE) Syndrome Protein RNF168

Abstract

Protein ubiquitination has emerged as a pivotal regulatory reaction that promotes cellular responses to DNA damage. With a goal to delineate the DNA damage signal transduction cascade, we systematically analyzed the human E2 ubiquitin- and ubiquitin-like-conjugating enzymes for their ability to mobilize the DNA damage marker 53BP1 onto ionizing radiation-induced DNA double strand breaks. An RNAi-based screen identified UBE2U as a candidate regulator of chromatin responses at double strand breaks. Further mining of the UBE2U interactome uncovered its cognate E3 RNF17 as a novel factor that, via the radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties (RIDDLE) syndrome protein RNF168, enforces DNA damage responses. Our screen allowed us to uncover new players in the mammalian DNA damage response and highlights the instrumental roles of ubiquitin machineries in promoting cell responses to genotoxic stress.

Somatic Mutations Detected in Parkinson Disease Could Affect Genes With a Role in Synaptic and Neuronal Processes

“…KCNK2 (or TREK-1) encodes a voltage-independent potassium channel essential in securing saltatory conduction at high frequency on myelinated afferent nerves ( Kanda et al, 2019 ). UBE2U , a ubiquitination enzyme, is a candidate regulator of chromatin responses at double strand breaks ( Guo et al, 2017 ), which are of fundamental relevance for gene expression in the brain ( Madabhushi et al, 2015 ). Furthermore, ubiquitination dysfunction has been linked to Parkinson ( Geisler et al, 2014 ) and Alzheimer ( Gómez-Ramos et al, 2015 ).…”

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“…WES identified two novel variants: c.62 A > G: p.(D21G) in STUM , and c.122 A > C: p.(E41A) in UBE2U . Of interest, UBE2U has been reported to regulate RNF168 [ 22 ], an E2-ubiquitin conjugating enzyme that has been associated with the R adiosensitivity I mmuno d eficiency D ysmorphic features and Le arning difficulties (RIDDLE) syndrome (OMIM 611943). Clinical assessment by a medical geneticist (OC) indicated this family shared some systemic dysmorphisms (short stature, small head circumference, low weight, hypertelorism) and behavioral/learning disabilities, similar to RIDDLE syndrome patients.…”

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“…The coded enzyme performs a central step in the ubiquitination reaction that targets a protein for degradation, a major factor for life and death of proteins (van Wijk and Timmers 2010). Protein ubiquitination is a pivotal regulatory reaction promoting the cellular responses to DNA damage (Guo et al 2017; Kazma et al 2012). UBE2U was recently identified as a positive regulator of TP53BP1, which promotes the formation of ionizing radiation-induced foci and thereby chromatin responses at DSBs in human cell lines (Guo et al 2017).…”

“…Protein ubiquitination is a pivotal regulatory reaction promoting the cellular responses to DNA damage (Guo et al 2017; Kazma et al 2012). UBE2U was recently identified as a positive regulator of TP53BP1, which promotes the formation of ionizing radiation-induced foci and thereby chromatin responses at DSBs in human cell lines (Guo et al 2017). E2 ligases are in general involved in multiple biological processes, for example UBE2T (1q32.1) promotes efficient DNA repair; UBE2B (5q31.1) is involved in UV mutagenesis, and UBE2N (12q22) is implicated in post-replication DNA repair following UV and ionizing radiations.…”