Ints10-KO Mouse

INTS10 is a subunit of the Integrator complex, which is involved in multiple crucial biological processes. The Integrator complex plays roles in 3'-ends processing of spliceosomal small nuclear RNAs (snRNAs) and regulating transcription of protein-coding genes by terminating transcription after unstable pausing [1]. INTS10, along with INTS13 and INTS14, forms a functional module within the Integrator complex. This module has affinity for nucleic acids, preferring RNA hairpins, and may bring the cleavage module and target transcripts into proximity [1].

Genetic polymorphisms in INTS10 are associated with the progression from persistent HBV infection to hepatocellular carcinoma (HCC). For example, the CT genotype of rs7000921 conferred a decreased risk of HBV-related HCC compared to the TT genotype. Also, an additive interaction was seen between the weighted genetic risk score (wGRS) generated from some INTS10 SNPs and drinking, and the interaction between wGRS and smoking approached near significance [2]. A novel INTS10-ALK fusion was reported in a case of N3 unresectable locally advanced lung adenocarcinoma, which achieved complete pathologic response to neoadjuvant crizotinib [3]. Mutations in the non-coding RNU4ATAC gene affect the splicing of INTS10 minor introns, reduce the levels of INTS10 protein, and alter the assembly of Integrator subunits [4]. Depletion of INTS10 upends neural traits and derails cells towards mesenchymal identity, suggesting its role in cell fate specification [5].

In conclusion, INTS10 is an important component of the Integrator complex, with its functions spanning from nucleic acid binding and transcription regulation to having implications in diseases like HCC and lung cancer. Studies on genetic polymorphisms and gene fusions related to INTS10, as well as its role in neural cell fate, contribute to our understanding of disease mechanisms and potential therapeutic targets.

References:

1. Sabath, Kevin, Stäubli, Melanie L, Marti, Sabrina, Moes, Murielle, Jonas, Stefanie. 2020. INTS10-INTS13-INTS14 form a functional module of Integrator that binds nucleic acids and the cleavage module. In Nature communications, 11, 3422. doi:10.1038/s41467-020-17232-2. https://pubmed.ncbi.nlm.nih.gov/32647223/

2. Wu, Yanmei, Lin, Zibo, Luo, Meihua, Chen, Sidong, Liu, Li. 2021. Effects of genetic polymorphisms in INTS10 and their interaction with environmental factors on progression from persistent HBV infection to hepatocellular carcinoma. In Molecular carcinogenesis, 60, 620-626. doi:10.1002/mc.23328. https://pubmed.ncbi.nlm.nih.gov/34133796/

3. Zhai, Xiaoqian, Wang, Ting, Lin, Yiyun, Zhou, Qinghua, Zhu, Daxing. 2023. Case report: Complete pathological admission in N3 unresectable locally advanced lung adenocarcinoma with a novel INTS10-ALK and EML4-ALK fusion after neoadjuvant crizotinib. In Frontiers in oncology, 13, 1104910. doi:10.3389/fonc.2023.1104910. https://pubmed.ncbi.nlm.nih.gov/37064118/

4. Almentina Ramos Shidi, Fatimat, Cologne, Audric, Delous, Marion, Mazoyer, Sylvie, Bordonné, Rémy. . Mutations in the non-coding RNU4ATAC gene affect the homeostasis and function of the Integrator complex. In Nucleic acids research, 51, 712-727. doi:10.1093/nar/gkac1182. https://pubmed.ncbi.nlm.nih.gov/36537210/

5. Zhang, Yingjie, Hill, Connor M, Leach, Kelsey A, Zucco, Avery, Gardini, Alessandro. 2024. The enhancer module of Integrator controls cell identity and early neural fate commitment. In Nature cell biology, 27, 103-117. doi:10.1038/s41556-024-01556-y. https://pubmed.ncbi.nlm.nih.gov/39592860/