Ercc8, also known as Cockayne syndrome type A (CSA) protein, plays critical roles in the nucleotide excision repair (NER) complex, especially in transcription-coupled nucleotide excision repair (TC-NER) pathway [2,3,4,5,6,7]. This pathway is crucial for maintaining DNA integrity by repairing damaged DNA, which is essential for normal cellular function and organism development. Genetic models, such as gene knockout mouse models, can be valuable for studying its functions.

In esophageal cancer, ERCC8 was identified as a novel cisplatin-resistant gene. It may contribute to cisplatin resistance through binding to damaged DNA for nucleotide excision repair, restoring basic DNA functions and cellular life activities. However, it has little effect on the proliferation and migration of esophageal cancer cells in vitro. Also, its expression is not associated with overall survival (OS), disease-specific survival (DSS), or first progression interval (FPI) in patients, but increased expression is associated with certain immune cells [1].

In a consanguineous Pakistani family, a novel homozygous missense mutation in ERCC8 co-segregated with cerebellar ataxia, expanding the role of ERCC8 mutations in autosomal-recessive cerebellar ataxias (ARCAs) [2]. A frameshift mutation in ERCC8 was found to be responsible for keratoconus with congenital cataracts in a Chinese family. The mutant proteins were degraded, reducing the DNA damage repair ability of corneal and lens cells [3]. Novel ERCC8 variants were identified in siblings with Cockayne syndrome without UV-sensitivity, emphasizing the importance of testing for ERCC8 variants even in incomplete CS phenotypes [4]. In a Chinese family with Cockayne syndrome, a compound heterozygous mutation of ERCC8 was identified, enlarging the genetic spectrum of the disease [5].

In gastric cancer, individual and joint expressions of ERCC8 and ERCC6 were associated with clinicopathological parameters and prognosis, and they may regulate gastric cancer progression through the PI3K/AKT/mTOR pathway [7]. ERCC8 was also identified as one of the pleiotropic genes shared between amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), and these candidate genes are mainly enriched in negative regulation of neuron projection development [8].

In conclusion, Ercc8 is essential for DNA repair through its role in the NER complex. Studies using various genetic models have revealed its significance in multiple disease areas, including cancer, ataxia, and eye diseases. Understanding Ercc8's functions can provide insights into disease mechanisms and potential therapeutic targets for these conditions.

References:

1. Sui, Xue, Tang, Xiaolong, Wu, Xi, Liu, Yongshuo. 2022. Identification of ERCC8 as a novel cisplatin-resistant gene in esophageal cancer based on genome-scale Nuclease technology screening. In Biochemical and biophysical research communications, 593, 84-92. doi:10.1016/j.bbrc.2022.01.033. https://pubmed.ncbi.nlm.nih.gov/35063774/

2. Gauhar, Zeeshan, Tejwani, Leon, Abdullah, Uzma, Lim, Janghoo, Raja, Ghazala K. 2022. A Novel Missense Mutation in ERCC8 Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani Family. In Cells, 11, . doi:10.3390/cells11193090. https://pubmed.ncbi.nlm.nih.gov/36231052/

3. Hao, Xiao-Dan, Yao, Yi-Zhi, Xu, Kai-Ge, Xu, Wen-Hua, Zhang, Jing-Jing. . Insufficient Dose of ERCC8 Protein Caused by a Frameshift Mutation Is Associated With Keratoconus With Congenital Cataracts. In Investigative ophthalmology & visual science, 63, 1. doi:10.1167/iovs.63.13.1. https://pubmed.ncbi.nlm.nih.gov/36454558/

4. Duong, Nguyen Thuy, Dinh, Tran Huu, Möhl, Britta S, Matsumoto, Naomichi, Meinke, Peter. 2022. Cockayne syndrome without UV-sensitivity in Vietnamese siblings with novel ERCC8 variants. In Aging, 14, 5299-5310. doi:10.18632/aging.204139. https://pubmed.ncbi.nlm.nih.gov/35748794/

5. Liu, Meng-Wei, Hu, Cheng-Feng, Jin, Jie-Yuan, Li, Ya-Li, Zhu, Lei. 2024. A compound heterozygous mutation of ERCC8 is responsible for a family with Cockayne syndrome. In Molecular biology reports, 51, 371. doi:10.1007/s11033-024-09235-9. https://pubmed.ncbi.nlm.nih.gov/38411728/

6. van Sluis, Marjolein, Yu, Qing, van der Woude, Melanie, Lans, Hannes, Marteijn, Jurgen A. 2024. Transcription-coupled DNA-protein crosslink repair by CSB and CRL4CSA-mediated degradation. In Nature cell biology, 26, 770-783. doi:10.1038/s41556-024-01394-y. https://pubmed.ncbi.nlm.nih.gov/38600236/

7. Chen, Jing, Li, Liang, Sun, Liping, Yuan, Yuan, Jing, Jingjing. 2021. Associations of individual and joint expressions of ERCC6 and ERCC8 with clinicopathological parameters and prognosis of gastric cancer. In PeerJ, 9, e11791. doi:10.7717/peerj.11791. https://pubmed.ncbi.nlm.nih.gov/34316408/

8. Tian, Ye, Ma, Guochen, Li, Haoqi, Xiong, Jingyuan, Cheng, Guo. 2023. Shared Genetics and Comorbid Genes of Amyotrophic Lateral Sclerosis and Parkinson's Disease. In Movement disorders : official journal of the Movement Disorder Society, 38, 1813-1821. doi:10.1002/mds.29572. https://pubmed.ncbi.nlm.nih.gov/37534731/