An ever-changing landscape in Roberts syndrome biology: Implications for macromolecular damage

Abstract

Roberts syndrome (RBS) is a rare developmental disorder that can include craniofacial abnormalities, limb malformations, missing digits, intellectual disabilities, stillbirth, and early mortality. The genetic basis for RBS is linked to autosomal recessive loss-of-function mutation of the establishment of cohesion (ESCO) 2 acetyltransferase. ESCO2 is an essential gene that targets the DNA-binding cohesin complex. ESCO2 acetylates alternate subunits of cohesin to orchestrate vital cellular processes that include sister chromatid cohesion, chromosome condensation, transcription, and DNA repair. Although significant advances were made over the last 20 years in our understanding of ESCO2 and cohesin biology, the molecular etiology of RBS remains ambiguous. In this review, we highlight current models of RBS and reflect on data that suggests a novel role for macromolecular damage in the molecular etiology of RBS.

Fig 1. ESCO2 regulates genome structure, function, and stability.

ESCO2 (Eco1/Ctf7 in yeast) is an acetyltransferase that modifies cohesin proteins during chromosome cohesion and condensation. Cohesin acetylation drives DNA damage-induced cohesion, which brings sister chromatids into close physical proximity to promote strand invasion during homologous recombination. ESCO2 acetylates cohesin to regulate chromatin looping, thereby modulating transcriptional outputs that bring enhancers (E) and promoters (P) into close proximity. Ac, acetylation; Ctf7, chromosome transmission fidelity 7 protein; Ecol, establishment of cohesion 1 protein; ESCO2, establishment of cohesion 2 protein.

Fig 2. ESCO2 mutation increases ROS production.

In normal cells (WT), DNA damage promotes ESCO2-dependent DIC and is efficiently repaired. DNA damage leads to transient up-regulation of ROS, which promotes DNA repair in combination with ESCO2 followed by reduction in ROS levels. In RBS, however, DNA damage leads to a dysregulated ROS positive feedback loop. Here, DNA damage up-regulates ROS, which is further induced by faulty DNA repair in the absence of proper ESCO2 function. Overproduction of ROS leads to oxidation of DNA and factors, which regulate the stress response, protein synthesis, and chromosome cohesion. The combination of reduced protein synthesis and elevated apoptosis results in RBS birth defects. DIC, damage-induced cohesion; ESCO2, establishment of cohesion 2; RBS, Roberts syndrome, ROS, reactive oxygen species; WT, wild type.