Nuclear protein in testis gene

The nuclear protein in testis gene (i.e. NUTM1 gene) encodes (i.e. directs the synthesis of) a 1,132-amino acid protein termed NUT[1] that is expressed almost exclusively in the testes, ovaries,[2] and ciliary ganglion (i.e. a parasympathetic ganglion of nerve cells located just behind the eye).[3] NUT protein facilitates the acetylation of chromatin (i.e. DNA-protein bundles) by histone acetyltransferase EP300 in testicular spermatids (cells that mature into sperms). This acetylation is a form of chromatin remodeling which compacts spermatid chromatin, a critical step required for the normal conduct of spermatogenesis, i.e. the maturation of spermatids into sperm.[4] Male mice that lacked the mouse Nutm1 gene using a gene knockout method had abnormally small testes, lacked sperm in their cauda epididymis (i.e. tail of the epididymis which contains sperm in fertile male mice), and were completely sterile.[5] These findings indicate that Nutm1 gene is essential for the development of normal fertility in male mice and suggest that the NUTM1 gene may play a similar role in men.[1][5]

The NUTM1 gene is located in band 14 on the long (or "q") arm of chromosome 15. In the early 1990s, this gene was implicated in the development of certain epithelial cell cancers that: a) occurred in the midline structures of young people, b) were rapidly fatal, and c) consisted of poorly differentiated (i.e. not resembling any particular cell type), immature-appearing cells containing a BRD4-NUTM1 fusion gene. BRD4 is the bromodomain-containing protein 4 gene. A fusion gene is an abnormal gene consisting of parts from two different genes that form as a result of a large scale gene mutation such as a chromosomal translocation, interstitial deletion, or inversion. The BRD4-NUTM1 fusion gene is a translocation that encodes a fusion protein that has merged most of the protein coding region of the NUTM1 gene with a large part of the BRD4 gene located in band 13 on the short (i.e. "q") arm of chromosome 19. This translocation is notated as t(15;19)(q13, p13.1).[2]

BRD4 protein recognizes acetylated lysine residues on proteins and by doing so participates in the regulation of DNA replication, DNA transcription, and thereby key cellular processes involved in the development of neoplasms (i.e. malignant or benign tissue growths).[6] The product of the BRD4-NUTM1 fusion gene, BRD4-NUT protein, stimulates the expression of at least 4 relevant genes, MYC, TP63, SOX2,[4] and MYB[7] in cultured cells. All four of these genes are oncogenes, i.e., genes that when overexpressed and/or overly active promote the development of certain types of cancers. Overexpression of the MYC and SOX2 genes can also act to maintain cells in an undifferentiated stem cell-like state similar to the cells in the neoplasms driven by the BRD4-NUTM1 fusion gene. It is generally accepted that the BRD4-NUT protein promotes these neoplasms by maintaining their neoplastic cells in a perpetually undifferentiated, proliferative state.[4] Further studies are needed to confirm and expand these views and to determine if any of the overexpressed gene products of the BRD4-NUT protein contribute to the development and/or progression, or can serve as targets for the treatment, of the neoplasms associated with the BRD4-NUTM1 fusion gene. These questions also apply to a wide range of neoplasms that have more recently been associated with the NUTM1 gene fused to other genes.[4][7]

  1. ^ a b McEvoy CR, Fox SB, Prall OW (June 2020). "Emerging entities in NUTM1-rearranged neoplasms". Genes, Chromosomes & Cancer. 59 (6): 375–385. doi:10.1002/gcc.22838. hdl:11343/275458. PMID 32060986. S2CID 211122796.
  2. ^ a b French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA (January 2003). "BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma". Cancer Research. 63 (2): 304–7. PMID 12543779.
  3. ^ Luo W, Stevens TM, Stafford P, Miettinen M, Gatalica Z, Vranic S (November 2021). "NUTM1-Rearranged Neoplasms-A Heterogeneous Group of Primitive Tumors with Expanding Spectrum of Histology and Molecular Alterations-An Updated Review". Current Oncology. 28 (6): 4485–4503. doi:10.3390/curroncol28060381. PMC 8628659. PMID 34898574.
  4. ^ a b c d Eagen KP, French CA (February 2021). "Supercharging BRD4 with NUT in carcinoma". Oncogene. 40 (8): 1396–1408. doi:10.1038/s41388-020-01625-0. PMC 7914217. PMID 33452461.
  5. ^ a b Shiota H, Barral S, Buchou T, Tan M, Couté Y, Charbonnier G, Reynoird N, Boussouar F, Gérard M, Zhu M, Bargier L, Puthier D, Chuffart F, Bourova-Flin E, Picaud S, Filippakopoulos P, Goudarzi A, Ibrahim Z, Panne D, Rousseaux S, Zhao Y, Khochbin S (September 2018). "Nut Directs p300-Dependent, Genome-Wide H4 Hyperacetylation in Male Germ Cells" (PDF). Cell Reports. 24 (13): 3477–3487.e6. doi:10.1016/j.celrep.2018.08.069. PMID 30257209. S2CID 52842598.
  6. ^ Jin W, Tan H, Wu J, He G, Liu B (January 2022). "Dual-target inhibitors of bromodomain-containing protein 4 (BRD4) in cancer therapy: Current situation and future directions". Drug Discovery Today. 27 (1): 246–256. doi:10.1016/j.drudis.2021.08.007. PMID 34438075. S2CID 237323653.
  7. ^ a b Hakun MC, Gu B (February 2021). "Challenges and Opportunities in NUT Carcinoma Research". Genes. 12 (2): 235. doi:10.3390/genes12020235. PMC 7915910. PMID 33562801.