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.
Highlights
Cockayne syndrome (CS) is a rare autosomal recessive disorder characterized by progressive neurodegeneration, mental retardation, developmental abnormalities, retinal degeneration, physical impairment, severe photosensitivity and premature aging [1]
Besides the TC-NER repair pathway, Cockayne syndrome protein B (CSB) plays a role in the repair of oxidative DNA lesions via base excision repair (BER), in interstrand crosslink (ICL) repair, in DNA double-strand break (DSB) repair and checkpoint activation [16,17,18,19,20,21]
Structural regulation of a protein through folding and refolding plays structural regulation of a protein folding andberefolding a critical role in protein function, specialthrough reference should made to plays its regulation v critical rolepost-translational in protein function, special reference should be made to its regulation via modifications
Summary
Cockayne syndrome (CS) is a rare autosomal recessive disorder characterized by progressive neurodegeneration, mental retardation, developmental abnormalities, retinal degeneration, physical impairment, severe photosensitivity and premature aging [1]. CSB protein is a major player of the transcription-coupled nucleotide excision repair (TC-NER or TCR) pathway, the subpathway of NER that removes transcriptionblocking DNA lesions from the transcribed strand of active genes. The role of CSB in TC-NER implicates RNA polymerase II (RNAPII) and together they have been implicated in the early steps of DNA damage recognition. CSB is required for the recruitment of the CSA/DDB1-Cul4ARBX1 E3 ubiquitin ligase (CRL4CSA ) in complex with the COP9 signalosome, key NER factors and chromatin modifiers such as p300 histone acetyltransferase and HMGN1 at the site of damage-stalled RNA Pol II [14]. Besides the TC-NER repair pathway, CSB plays a role in the repair of oxidative DNA lesions via BER, in interstrand crosslink (ICL) repair, in DNA double-strand break (DSB) repair and checkpoint activation [16,17,18,19,20,21]. There is a number of studies indicating that CSB is involved in transcription, in chromatin remodeling, in nucleolar rDNA transcription by RNA polymerase I, in mitochondrial function, in enhancement of the p53–chromatin association, in p53 ubiquitination, in cell division completion and in telomere maintenance [22,23,24,25,26,27,28,29,30]
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