Cockayne Syndrome Group B (CSB): The Regulatory Framework Governing the Multifunctional Protein and Its Plausible Role in Cancer

Abstract

Cockayne syndrome (CS) is a DNA repair syndrome characterized by a broad spectrum of clinical manifestations such as neurodegeneration, premature aging, developmental impairment, photosensitivity and other symptoms. Mutations in Cockayne syndrome protein B (CSB) are present in the vast majority of CS patients and in other DNA repair-related pathologies. In the literature, the role of CSB in different DNA repair pathways has been highlighted, however, new CSB functions have been identified in DNA transcription, mitochondrial biology, telomere maintenance and p53 regulation. Herein, we present an overview of identified structural elements and processes that impact on CSB activity and its post-translational modifications, known to balance the different roles of the protein not only during normal conditions but most importantly in stress situations. Moreover, since CSB has been found to be overexpressed in a number of different tumors, its role in cancer is presented and possible therapeutic targeting is discussed.

Keywords: CSB; Cockayne syndrome; Cockayne syndrome pathologies; Cockayne syndrome protein B; ERCC6; cancer.

Figure 1

(A) Schematic representation of Cockayne syndrome protein B (CSB) structure. (B) Crystal structures of ERCC6 proteins (i) A ribbon representation of the N-terminal coiled coil domain of the human ERCC6 (PDB id: 4cvo; Uniprot id: q03468); (ii) the structure of the winged helix domain of a specific ERCC6 variant (PDB id: 6a6i; Uniprot id: q59ff6) in complex with ubiquitin (ERCC6 ribbon: blue, ubiquitin ribbon: red) [46,47].

Figure 2

Multifunctional role of CSB (A) and related pathologies (B). Abbreviations: TC-NER: Transcription-Coupled Nucleotide Excision Repair, BER: Base Excision Repair, NHEJ: Non-Homologous End Joining, HR: Homologous Recombination, DSBs: Double-Strand Breaks, COFS: Cerebro-Oculo-Facio-Skeletal Syndrome, UVSS: UV-Sensitive Syndrome.