Multiple interaction partners for Cockayne syndrome proteins: implications for genome and transcriptome maintenance

Abstract

Cockayne syndrome (CS) is characterized by progressive multisystem degeneration and is classified as a segmental premature aging syndrome. The majority of CS cases are caused by defects in the CS complementation group B (CSB) protein and the rest are mainly caused by defects in the CS complementation group A (CSA) protein. Cells from CS patients are sensitive to UV light and a number of other DNA damaging agents including various types of oxidative stress. The cells also display transcription deficiencies, abnormal apoptotic response to DNA damage, and DNA repair deficiencies. Herein we have critically reviewed the current knowledge about known protein interactions of the CS proteins. The review focuses on the participation of the CSB and CSA proteins in many different protein interactions and complexes, and how these interactions inform us about pathways that are defective in the disease.

Figure 1

Motifs in the CSB protein. CSB harbors an acidic region and a glycine rich stretch with unknown function and two putative nuclear localization sequences (NLS) and a nucleotide binding domain (NTB). An ATPase domain including seven helicase-like motifs is present in the center of the protein, with the ATPase activity of CSB being necessary for the involvement in TC-NER. An ubiquitin binding domain (UBD) is found in the C-terminal with likely relevance for involvement in TC-NER. B) The N-terminal of CSB has been found to interact with proteins involved in BER.

Figure 2

CSB interactions with BER core participants. The interactions between CSB and the DNA glycosylase NEIL1, and co-existence of CSB in complex with OGG1 affects the repair of oxidative lesions at the incision/excision steps in BER. The interaction with APE1 stimulates the formation of single strand breaks ready for elongation by DNA polymerases. PARP-1 is known to bind single stand breaks.

Figure 3

Proteins interacting or in complex with CSB. CSB directly interacts (showed in black) or is found in complex with (shown in gray) proteins involved in transcription, TC-NER and BER, based on the literature described in the text. The great overlap between functionality of the proteins interacting with CSB supports a complex multifunctional background for Cockayne Syndrome.

Figure 4

Motifs in the CSA protein. Seven Trp-Asp motifs (WD) have been identified in CSA, forming circularized beta propeller structures serving as scaffold for protein-protein interactions.

Figure 5

Proteins directly interacting or in complex with CSA. CSA directly interacts (showed in black) or is found in complex with (shown in gray) proteins involved in transcription, TC-NER and ubiquitination, based on the literature described in the text. The majority of proteins found in complex with CSA and with functional effect of the interaction are proteins involved in ubiquitination of proteins in response to cellular damage. Additionally, proteins involved in transcription and TC-NER by chromatin remodeling is found to depend on CSA for their recruitment.

Figure 6

Roles of CSB in maintenance of cellular homeostasis. CSB are involved in multiple functions in the cell all aimed to maintain cellular homeostasis, In the nucleus CSB is involved in transcription thereby involved in maintaining the transcriptome whereas involvement in TC-NER and BER both are related to genomic stability. In the mitochondria, CSB is involved in maintaining the transcriptome through transcription and DNA stability by mtBER. Additionally, CSB are involved in mitochondrial autophagy and bioenergetics.