ERCC8

ERCC8, also known as CSA, is a human gene that encodes the CSA protein, a central component of transcription-coupled nucleotide excision repair (TC-NER). CSA functions as a substrate receptor within the CRL4A-DDB1 ubiquitin ligase complex and plays a key role in recognizing and processing DNA lesions that block transcription. In response to DNA damage such as ultraviolet irradiation, CSA partners with CSB (ERCC6) to recruit repair factors to stalled RNA polymerase II, promoting the ubiquitination and turnover of transcription-related proteins and thereby enabling efficient repair of transcribed genes and resumption of transcription.

Mutations in ERCC8 cause Cockayne syndrome type A (CS-A), a rare autosomal recessive disorder. CS-A is characterized by growth retardation, neurodevelopmental abnormalities, photosensitivity, premature aging features, microcephaly, hearing and vision problems, dental anomalies, and skeletal abnormalities. The disorder arises from defects in TC-NER, leading to impaired repair of transcription-blocking DNA lesions and consequent cellular sensitivity to DNA damage. Unlike some other DNA repair disorders, Cockayne syndrome patients show limited cancer predisposition, with a phenotype dominated by developmental and neurological symptoms.

Structure and interactions: CSA is a nuclear protein that contains WD40 repeats and associates with the CRL4A complex, including CUL4A and DDB1. Through this complex, CSA targets specific substrates for ubiquitination, notably CSB and components of the transcription machinery, coordinating chromatin remodeling and the repair process during TC-NER.

Clinical relevance: ERCC8 testing is used in the diagnosis of Cockayne syndrome. Understanding CSA function clarifies the link between transcription-coupled repair defects and the neurodevelopmental and aging features observed in CS-A.