Ercc8, also known as Cockayne syndrome type A (CSA) protein, plays critical roles in the nucleotide excision repair complex, particularly in transcription-coupled nucleotide excision repair (TC-NER) pathway [2,5,6,7]. This pathway is essential for repairing DNA damage, which is crucial for maintaining basic DNA functions and cellular life activities [1].

In esophageal cancer, ERCC8 was identified as a novel cisplatin-resistant gene. It may contribute to cisplatin resistance by binding to damaged DNA for nucleotide excision repair, yet has little effect on the proliferation and migration of esophageal cancer cells in vitro [1].

In autosomal-recessive cerebellar ataxias (ARCAs), a novel homozygous missense mutation in ERCC8 was found to co-segregate with the disease, expanding the role of ERCC8 mutations in ARCAs [2].

A frameshift mutation in ERCC8 was associated with keratoconus and congenital cataracts, as it led to an insufficient dose of the ERCC8 protein, reducing DNA damage repair ability in corneal and lens cells [3].

Also, in Cockayne syndrome, novel ERCC8 variants were identified in patients, highlighting the importance of testing for ERCC8 variants even without a complete CS phenotype [4,5].

In gastric cancer, individual and joint expressions of ERCC8 with ERCC6 were associated with clinicopathological parameters and prognosis, and they were mainly involved in the nucleotide excision repair pathway and regulation of the PI3K/AKT/mTOR pathway [7].

Additionally, ERCC8 was identified as one of the comorbid genes between amyotrophic lateral sclerosis and Parkinson's disease, and these candidate genes were enriched in negative regulation of neuron projection development [8].

In conclusion, ERCC8 is vital for DNA repair through its role in the nucleotide excision repair complex. Studies using various genetic models, though not specifically KO/CKO mouse models in the provided references, have revealed its significance in multiple disease conditions such as esophageal cancer, ARCAs, keratoconus with congenital cataracts, Cockayne syndrome, gastric cancer, and the comorbidity of amyotrophic lateral sclerosis and Parkinson's disease. Understanding ERCC8's function provides insights into disease mechanisms and potential therapeutic targets.