Human SIRT1 Alternate Splicing

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Human SIRT1 Alternate Splicing

The human sirtuin 1 (SIRT1) gene is a member of the sirtuin family of genes known for deacetylating multiple histones and other proteins (Zhang, et al. 2021). It is a gene that conserves deeply rooted functionality, likely from primordial times (Elibol, & Kilic, 2018 ;SInclair, 2019). As of this date SIRT1 is identified as having 36 functional areas, affects at least 41 different pathways, interacts with at minimum 404 different proteins, and is involved in at minimum 131 varying molecular processes (National Center for Biotechnology Information (NCBI), 2022). Variants of the gene are found throughout the body in multiple tissues at varying levels, depending on tissue type and age of the individual (Zhang, et al. 2021), and are active in at least 23 cellular components including the nucleus, cytoplasm, and mitochondrian (NCBI, 2022). 

The human SIRT1 gene is located on chromosome 10 (10q21.3), occupies base pairs 67,884,656 - 67,918,390, has 11 identified exons (possibly 21 alternative exons), and has 15 distinct introns (Alliance of Genome Resources, 2008; NCBI, 2010; NCBI, 2022; Zhang, et al. 2021). Three generalized variants of the SIRT1 gene (v1, v2, and v3) are recognized in human tissue. Zhang et al. (2021) notes that of the 11 identified exons, until recently only nine were identified, and thus in their paper they number the exons by relative position as ex1, ex1', ext2, ex3, ex4, ex4', ex5, ex7, ex8, and ex9. Note the prime marks at ex1' and ex4'. This same numbering scheme will be used for the following dialog. Variant 1 of the SIRT1 gene uses all of the exons except ex1' and ex4'. Variant 2 skips ex1, starts with ex1', includes ex2, skips ex3, and transcribes the remaining ext4 through ex9. Variant 3 skips ex1 through ex3, begins with ex4, includes ex4', and continues transcription of ex5 through ex9.  All three gene variants use ex4 through ex9, only variant 2 uses ex1' and only variant 3 uses ex4'.  The skipping of ex1 and ex3 however has impactful consequences as ex1 and ex3 contain the only nuclear localization signals (NLS) in the gene, one in each exon. This means that variants 2 and variant 3 are localized to the cytoplasm whereas variant 1 is localized to the nucleus (Zhang, et al. 2021). 

Variation in the transcription also occurs at the beginning 5' end and the ending 3' end of the transcripts. Analysis of past transcriptions reveals five potential promoters, a multitude of potential transcript starting point base pairs, and six alternative polyadenylation sites (NCBI, 2010; NCBI 2022). All told, the potential variation in transcription has produced at least five verified good proteins, however it is likely that many more exist depending on the specific tissue type and age of the test subject (NCBI, 2010; Zhang, 2021). Thus far, the SIRT1 gene has only shown to skip exons with no indication of exon swapping or exchange. It is reasonably assured that as time passes new variants and subvariants will be identified, especially as we progress into the age of bioinformatics. 

References

Alliance of Genome Resources. (2008). SIRT1 Homo sapiens. Retrieved on October 2, 2022 from www.alliancegenome.org/gene/HGNC:14929#summary 

Elibol, B., & Kilic, U. (2018). High Levels of SIRT1 Expression as a Protective Mechanism Against Disease-Related Conditions. Frontiers in Endocrinology, 9, 614. doi.org/10.3389/fendo.2018.00614

Sinclair, D.A., & LaPlante, M. D. (2019). Lifespan: Why We Age―and Why We Don't Have To. Atria Books.

National Center for Biotechnology Information. (2010). Homo sapiens Gene SIRT1, Encoding Sirtuin 1. AceView. Retrieved on October 2, 2022 from www.ncbi.nlm.nih.gov/IEB/Research/Acembly/av.cgi?db=human&q=SIRT1

National Center for Biotechnology Information. (2022, September 25). SIRT1 sirtuin 1 [ Homo sapiens (human) ]. National Library of Medicine. Retrieved on September 22, 2022 from www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=23411

Zhang, X., Ameer, F. S., Azhar, G., & Wei, J. Y. (2021). Alternative Splicing Increases Sirtuin Gene Family Diversity and Modulates Their Subcellular Localization and Function. International Journal of Molecular Sciences, 22(2), 473. doi.org/10.3390/ijms22020473


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