Regulation of the polycomb protein Ring1B by self-ubiquitination or by E6-AP may have implications to the pathogenesis of Angelman syndrome.

The polycomb repressive complex (PRC) 1 protein Ring1B is an ubiquitin ligase that modifies nucleosomal histone H2A, a modification which plays a critical role in regulation of gene expression. We have shown that self-ubiquitination of Ring1B generates multiply branched, "noncanonical" polyubiquitin chains that do not target the ligase for degradation, but rather stimulate its activity toward histone H2A. This finding implies that Ring1B is targeted by a heterologous E3. In this study, we identified E6-AP (E6-associated protein) as a ligase that targets Ring1B for "canonical" ubiquitination and subsequent degradation. We further demonstrated that both the self-ubiquitination of Ring1B and its modification by E6-AP target the same lysines, suggesting that the fate of Ring1B is tightly regulated (e.g., activation vs. degradation) by the type of chains and the ligase that catalyzes their formation. As expected, inactivation of E6-AP affects downstream effectors: Ring1B and ubiquitinated H2A levels are increased accompanied by repressed expression of HoxB9, a PRC1 target gene. Consistent with these findings, E6-AP knockout mice display an elevated level of Ring1B and ubiquitinated histone H2A in various tissues, including cerebellar Purkinje neurons, which may have implications to the pathogenesis of Angelman syndrome, a neurodevelopmental disorder caused by deficiency of E6-AP in the brain.

The natural history of curve behavior after brace removal in adolescent idiopathic scoliosis: a literature review.

PURPOSE: Brace treatment is the most common nonoperative treatment to prevent curve progression in adolescent idiopathic scoliosis (AIS). The goal of this review and analysis is to characterize curve behavior after completion of brace treatment and to identify factors that may facilitate the estimation of long-term curve progression. METHOD: A review of the English language literature was completed using the MEDLINE (PUBMED) database of publications after 1990 until September 2020. Studies were included if they detailed a minimum of 1 year post-brace removal follow-up of AIS patients. Data retrieved from the articles included Cobb angle measurements of the major curves at "in-brace," weaning, and follow-up visit(s) for all patients described and for subset populations. RESULTS: From 75 articles, 18 relevant studies describing a follow-up period of 1-25 years following brace removal were included in the analyses. The reviewed literature demonstrates that curves continue to progress after brace treatment is completed with three main phases of progression: (i) immediate (upon brace removal) where a mean curve progression of 7° occurs; (ii) short term (within five years of brace removal) where a relatively high progression rate is evident (0.8°/year); and (iii) long term (more than five years after brace removal) where the progression rate slows (0.2°/year). The magnitude and rate of curve progression is mainly dependent on the degree of curve at weaning as curves weaned at < 25° progress substantially less than curves weaned at ≥ 25° at 25 years. CONCLUSION: Curves continue to progress after brace removal and the rate and magnitude of progression are associated with the curve size at weaning, with larger curves typically exhibiting more rapid and severe progression. This analysis provides physicians and patients the ability to estimate long-term curve size based on the curve size at the time of weaning. LEVEL OF EVIDENCE: IV.

Regulation of the Polycomb protein RING1B ubiquitination by USP7.

The E3 ubiquitin ligase RING1B plays an important role in Polycomb-mediated gene silencing by monoubiquitinating histone H2A. Both the activity and stability of RING1B are controlled by ubiquitination in two distinct manners. Self ubiquitination of RING1B generates K6, K27 and K48-based mixed polyubiquitin chain, and is required for its activity as a ligase. On the other hand, its proteasomal degradation is mediated by another ligase; E6-AP catalyzes the formation of K48-based chains. Since these two modes of ubiquitination target the same lysine residues and are therefore mutually exclusive, an important mode of regulation of RING1B should be at the level of deubiquitination. Here we identify USP7 as a deubiquitinating enzyme that regulates the ubiquitination state of RING1B. RING1B interacts with USP7, which is mediated in part by its RING domain. In addition, USP7 was found in a complex with other Polycomb proteins, suggesting a broad role in regulating these complexes. Although, USP7 directly and specifically deubiquitinates RING1B in vitro and in vivo, it does not discriminate between the activating and proteolysis-targeting modes of ubiquitination, and therefore has a stabilizing effect on RING1B.

Brace treatment in adolescent idiopathic scoliosis: risk factors for failure-a literature review.

Brace treatment is the most common nonoperative treatment for the prevention of curve progression in adolescent idiopathic scoliosis. The success reported in level 1 and 2 clinical trials is approximately 75%. The aim of this review was to identify the main risk factors that significantly reduce success rate of brace treatment. A literature search using the MEDLINE and Embase databases was conducted. Studies were included if they identified specific risk factor(s) for curve progression. Studies that looked at nighttime braces, superiority of one type of brace over another, the effect of physical therapy on brace performance, cadaver or nonhuman studies were excluded. A total of 1,022 articles were identified of which 25 met all of the inclusion criteria. Seven risk factors were identified: Poor brace compliance (eight studies), lack of skeletal maturity (six studies), Cobb angle over a certain threshold (six studies), poor in-brace correction (three studies), vertebral rotation (four studies), osteopenia (two studies), and thoracic curve type (two studies). Three risk factors were highly repeated in the literature which identified specific subgroups of patients who have a much higher risk to fail brace treatment and to progress to fusion. This data demonstrates that 60% to 70% of the patients referred to bracing are Risser 0 and 30% to 70% of this group will not wear the brace enough to ensure treatment efficacy. Furthermore, Risser 0 patients who reach the accelerated growth phase with a curve ≥40° are at 70% to 100% risk of curve progression to the fusion surgical threshold despite proper brace wear. Skeletally immature patients with relatively large magnitude scoliosis who are noncompliant are at a higher risk of failing brace treatment.