MIR34A explained

MicroRNA 34a (miR-34a) is a microRNA that in humans is encoded by the MIR34A gene.^[1]

Function

microRNAs (miRNAs) are short (20–24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding.

The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products.

The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop.

Repair of DNA damage

Expression of miR-34A is markedly up-regulated in hematopoietic stem cells (HSCs) from mice subjected to ionizing radiation.^[2] HSCs that are deficient in miR-34A have decreased expression of genes involved in the DNA repair processes of homologous recombination and non-homologous end joining.^[2] These and other findings demonstrate that miR-34A contributes to the survival of HSCs after irradiation.^[2]

Clinical relevance

miR-34a suppresses the gene expression of NAMPT, which encodes nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the nicotinamide adenine dinucleotide (NAD) salvage pathway, resulting in reduced levels of NAD.^[3] miR-34a suppression of NAMPT gene expression also reduces levels of sirtuin 1. Aging and obesity increase levels of miR-34a. The pro-inflammatory transcription factor NF-κB (increasingly expressed with obesity and aging)^[4] increases miR-34a expression by binding to its promoter region.^[5] Inhibition of miR-34a in diet-induced obese mice restored levels of NAMPT and NAD, reducing inflammation and improving glucose tolerance.^[6]

miR-34a represses the translation of sirtuin 1 (SIRT1) in liver by binding to the 3′-UTR region of SIRT1 messenger RNA, contributing to metabolic syndrome.^{[7] [8]} Downregulation of SIRT1 by miR-34a promotes cellular senescence and inflammation in vascular smooth muscle cells of old mice, similar to reduced SIRT1 in vascular smooth muscle cells in humans.^[9] Impaired endothelial-dependent vasorelaxation caused by miR-34a can be ameliorated by SIRT1 overexpression.

Further reading

• Pang RT, Leung CO, Ye TM, Liu W, Chiu PC, Lam KK, Lee KF, Yeung WS . MicroRNA-34a suppresses invasion through downregulation of Notch1 and Jagged1 in cervical carcinoma and choriocarcinoma cells . Carcinogenesis . 31 . 6 . 1037–44 . June 2010 . 20351093 . 10.1093/carcin/bgq066 . free .
• Lim LP, Glasner ME, Yekta S, Burge CB, Bartel DP . Vertebrate microRNA genes . Science . 299 . 5612 . 1540 . March 2003 . 12624257 . 10.1126/science.1080372 . 37750545 .
• Zauli G, Voltan R, di Iasio MG, Bosco R, Melloni E, Sana ME, Secchiero P . miR-34a induces the downregulation of both E2F1 and B-Myb oncogenes in leukemic cells . Clinical Cancer Research . 17 . 9 . 2712–24 . May 2011 . 21367750 . 10.1158/1078-0432.CCR-10-3244 . free .
• Forte E, Salinas RE, Chang C, Zhou T, Linnstaedt SD, Gottwein E, Jacobs C, Jima D, Li QJ, Dave SS, Luftig MA . The Epstein-Barr virus (EBV)-induced tumor suppressor microRNA MiR-34a is growth promoting in EBV-infected B cells . Journal of Virology . 86 . 12 . 6889–98 . June 2012 . 22496226 . 3393554 . 10.1128/JVI.07056-11 .
• Navarro F, Gutman D, Meire E, Cáceres M, Rigoutsos I, Bentwich Z, Lieberman J . miR-34a contributes to megakaryocytic differentiation of K562 cells independently of p53 . Blood . 114 . 10 . 2181–92 . September 2009 . 19584398 . 10.1182/blood-2009-02-205062 .
• Welch C, Chen Y, Stallings RL . MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells . Oncogene . 26 . 34 . 5017–22 . July 2007 . 17297439 . 10.1038/sj.onc.1210293 . 18158985 .
• Siemens H, Jackstadt R, Hünten S, Kaller M, Menssen A, Götz U, Hermeking H . miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions . Cell Cycle . 10 . 24 . 4256–71 . December 2011 . 22134354 . 10.4161/cc.10.24.18552 . free .
• Yamamura S, Saini S, Majid S, Hirata H, Ueno K, Deng G, Dahiya R . MicroRNA-34a modulates c-Myc transcriptional complexes to suppress malignancy in human prostate cancer cells . PLOS ONE . 7 . 1 . e29722 . 2012 . 22235332 . 3250472 . 10.1371/journal.pone.0029722 . 2012PLoSO...729722Y . free .
• Lou WJ, Chen Q, Liu L, Qian C . [miR-34s--a tumor suppression protein p53 highly related microRNA] . Yi Chuan = Hereditas . 32 . 5 . 423–30 . May 2010 . 20466628 . 10.3724/SP.J.1005.2010.00423 . free .

Notes and References

1. Web site: Entrez Gene: MicroRNA 34a .
2. Zeng H, Hu M, Lu Y, Zhang Z, Xu Y, Wang S, Chen M, Shen M, Wang C, Chen F, Du C, Tang Y, Su Y, Chen S, Wang J . 6 . MicroRNA 34a promotes ionizing radiation-induced DNA damage repair in murine hematopoietic stem cells . FASEB Journal . 33 . 7 . 8138–8147 . July 2019 . 30922079 . 10.1096/fj.201802639R . free .
3. Yaku K, Okabe K, Nakagawa T . NAD Metabolism: Implications in Aging and Longevity . . 47 . 1–17 . 2018 . 10.1016/j.arr.2018.05.006 . 29883761. 47002665 .
4. Kauppinen A, Suuronen T, Ojala J, Kaarniranta K, Salminen A . Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders . . 25 . 10 . 1939–1948 . 2013 . 10.1016/j.cellsig.2013.06.007 . 23770291.
5. de Gregorio E, Colell A, Morales A, Marí M . Relevance of SIRT1-NF-κB Axis as Therapeutic Target to Ameliorate Inflammation in Liver Disease . . 21 . 11 . 3858 . 2020 . 10.3390/ijms21113858 . 7312021 . 32485811. free .
6. Garten A, Schuster S, Penke M, Kiess W . Physiological and pathophysiological roles of NAMPT and NAD metabolism . . 11 . 9 . 535–546 . 2015 . 10.1038/nrendo.2015.117 . 26215259. 11670137 .
7. Cantó C, Auwerx J . Targeting sirtuin 1 to improve metabolism: all you need is NAD(+)? . . 64 . 1 . 166–187 . 2012 . 10.1124/pr.110.003905 . 3616312 . 22106091.
8. Imai S, Yoshino J . The importance of NAMPT/NAD/SIRT1 in the systemic regulation of metabolism and ageing . . 15 . Suppl 3 . 26–33 . 2013 . 10.1111/dom.12171 . 3819727 . 24003918.
9. D'Onofrio N, Servillo L, Balestrieri ML . SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection . . 28 . 8 . 711–732 . 2018 . 10.1089/ars.2017.7178 . 5824538 . 28661724.