CYLD (gene) explained

The CYLD lysine 63 deubiquitinase gene, also termed the CYLD gene,^[1] CYLD is an evolutionary ancient gene found to be present as far back on the evolutionary scale as in sponges.^[2] In humans, this gene is located in band 12.1 on the long (or "q") arm of chromosome 16^[3] and is known to code (i.e. direct the production of) multiple proteins through the process of alternative splicing.^[4]

The CYLD gene in known to code for a cytoplasmic protein, termed CYLD lysine 63 deubiquitinase (here termed CYLD protein), which has three cytoskeletal-associated protein-glycine-conserved (CAP-GLY) domains (areas or the protein controlling critical functions^[5]). CYLD protein is a deubiquitinating enzyme, i.e. a protease that removes ubiquitin from certain proteins and thereby regulates these proteins' activities. CYLD protein removes ubiquitin from proteins involved in regulating the NF-κB, Wnt, notch, TGF-β, and JNK^[6] cell signaling pathways; these pathways normally act to regulate hair formation, cell growth, cell survival, inflammatory responses, and/or tumor development.^[6]

The CYLD gene is classified as a tumor suppressor gene, i.e. a gene that regulates cell growth and when inactivated by a mutation leads to uncontrolled cell growth and the formation of tumors.^[7] Inactivating mutations in this gene occur in essentially all cases of the CYLD cutaneous syndrome, a hereditary disorder in which individuals develop multiple skin tumors. The CYLD cutaneous syndrome includes three somewhat different forms of the disease: the multiple familial trichoepithelioma-type, Brooke–Spiegler syndrome-type, and familial cylindromatosis-type.^[8] CYLD gene mutations are also associated with T-Cell Acute Lymphoblastic Leukemia,^[7] multiple myeloma, hepatocellular carcinoma, neuroblastoma, pancreatic cancer,^[9] uterine cancer, stomach cancer, colon cancer, lung cancer, and human papillomavirus-associated cancers.^[6]

Further reading

• Nakajima D, Okazaki N, Yamakawa H, Kikuno R, Ohara O, Nagase T . Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones . DNA Research . 9 . 3 . 99–106 . June 2002 . 12168954 . 10.1093/dnares/9.3.99 . 10.1.1.500.923 .
• Lian F, Cockerell CJ . Cutaneous appendage tumors: familial cylindromatosis and associated tumors update . Advances in Dermatology . 21 . 217–34 . 2006 . 16350444 . 10.1016/j.yadr.2005.06.005 .
• Biggs PJ, Wooster R, Ford D, Chapman P, Mangion J, Quirk Y, Easton DF, Burn J, Stratton MR . Familial cylindromatosis (turban tumour syndrome) gene localised to chromosome 16q12-q13: evidence for its role as a tumour suppressor gene . Nature Genetics . 11 . 4 . 441–3 . December 1995 . 7493027 . 10.1038/ng1295-441 . 33637152 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Biggs PJ, Chapman P, Lakhani SR, Burn J, Stratton MR . The cylindromatosis gene (cyld1) on chromosome 16q may be the only tumour suppressor gene involved in the development of cylindromas . Oncogene . 12 . 6 . 1375–7 . March 1996 . 8649842 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Nagase T, Ishikawa K, Suyama M, Kikuno R, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O . Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro . DNA Research . 5 . 6 . 355–64 . December 1998 . 10048485 . 10.1093/dnares/5.6.355 . free .
• Thomson SA, Rasmussen SA, Zhang J, Wallace MR . A new hereditary cylindromatosis family associated with CYLD1 on chromosome 16 . Human Genetics . 105 . 1–2 . 171–3 . 1999 . 10480375 . 10.1007/s004399900077 .
• Bignell GR, Warren W, Seal S, Takahashi M, Rapley E, Barfoot R, Green H, Brown C, Biggs PJ, Lakhani SR, Jones C, Hansen J, Blair E, Hofmann B, Siebert R, Turner G, Evans DG, Schrander-Stumpel C, Beemer FA, van Den Ouweland A, Halley D, Delpech B, Cleveland MG, Leigh I, Leisti J, Rasmussen S . Identification of the familial cylindromatosis tumour-suppressor gene . Nature Genetics . 25 . 2 . 160–5 . June 2000 . 10835629 . 10.1038/76006 . 22829077 .
• Zhang QH, Ye M, Wu XY, Ren SX, Zhao M, Zhao CJ, Fu G, Shen Y, Fan HY, Lu G, Zhong M, Xu XR, Han ZG, Zhang JW, Tao J, Huang QH, Zhou J, Hu GX, Gu J, Chen SJ, Chen Z . Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells . Genome Research . 10 . 10 . 1546–60 . October 2000 . 11042152 . 310934 . 10.1101/gr.140200 .
• Trompouki E, Hatzivassiliou E, Tsichritzis T, Farmer H, Ashworth A, Mosialos G . CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members . Nature . 424 . 6950 . 793–6 . August 2003 . 12917689 . 10.1038/nature01803 . 2003Natur.424..793T . 4424549 . 21.11116/0000-0007-948F-1 . free .
• Brummelkamp TR, Nijman SM, Dirac AM, Bernards R . Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB . Nature . 424 . 6950 . 797–801 . August 2003 . 12917690 . 10.1038/nature01811 . 2003Natur.424..797B . 1874/17767 . 4416878 . free .
• Kovalenko A, Chable-Bessia C, Cantarella G, Israël A, Wallach D, Courtois G . The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination . Nature . 424 . 6950 . 801–5 . August 2003 . 12917691 . 10.1038/nature01802 . 2003Natur.424..801K . 4397177 .
• Hu G, Onder M, Gill M, Aksakal B, Oztas M, Gürer MA, Celebi JT . A novel missense mutation in CYLD in a family with Brooke-Spiegler syndrome . The Journal of Investigative Dermatology . 121 . 4 . 732–4 . October 2003 . 14632188 . 10.1046/j.1523-1747.2003.12514.x . free . 20.500.12648/7847 . free .
• Regamey A, Hohl D, Liu JW, Roger T, Kogerman P, Toftgard R, Huber M . The tumor suppressor CYLD interacts with TRIP and regulates negatively nuclear factor kappaB activation by tumor necrosis factor . The Journal of Experimental Medicine . 198 . 12 . 1959–64 . December 2003 . 14676304 . 2194148 . 10.1084/jem.20031187 .
• Zhang XJ, Liang YH, He PP, Yang S, Wang HY, Chen JJ, Yuan WT, Xu SJ, Cui Y, Huang W . Identification of the cylindromatosis tumor-suppressor gene responsible for multiple familial trichoepithelioma . The Journal of Investigative Dermatology . 122 . 3 . 658–64 . March 2004 . 15086550 . 10.1111/j.0022-202X.2004.22321.x . free .
• Jono H, Lim JH, Chen LF, Xu H, Trompouki E, Pan ZK, Mosialos G, Li JD . NF-kappaB is essential for induction of CYLD, the negative regulator of NF-kappaB: evidence for a novel inducible autoregulatory feedback pathway . The Journal of Biological Chemistry . 279 . 35 . 36171–4 . August 2004 . 15226292 . 10.1074/jbc.M406638200 . free . 21.11116/0000-0007-9489-7 . free .

Notes and References

1. Web site: Symbol report for CYLD . www.genenames.org/ . 20 June 2019 . 1.
2. Hadweh P, Chaitoglou I, Gravato-Nobre MJ, Ligoxygakis P, Mosialos G, Hatzivassiliou E . Functional analysis of the C. elegans cyld-1 gene reveals extensive similarity with its human homolog . PLOS ONE . 13 . 2 . e0191864 . 2018 . 29394249 . 5796713 . 10.1371/journal.pone.0191864 . 2018PLoSO..1391864H . free .
3. Arruda AP, Cardoso-Dos-Santos AC, Mariath LM, Feira MF, Kowalski TW, Bezerra KR, da Silva LA, Ribeiro EM, Schuler-Faccini L . A large family with CYLD cutaneous syndrome: medical genetics at the community level . Journal of Community Genetics . 11 . 3 . 279–284 . July 2020 . 31792733 . 7295879 . 10.1007/s12687-019-00447-2 .
4. Web site: Entrez Gene: CYLD cylindromatosis (turban tumor syndrome).
5. Weisbrich A, Honnappa S, Jaussi R, Okhrimenko O, Frey D, Jelesarov I, Akhmanova A, Steinmetz MO . Structure-function relationship of CAP-Gly domains . Nature Structural & Molecular Biology . 14 . 10 . 959–67 . October 2007 . 17828277 . 10.1038/nsmb1291 . 37088265 .
6. Cui Z, Kang H, Grandis JR, Johnson DE . CYLD Alterations in the Tumorigenesis and Progression of Human Papillomavirus-Associated Head and Neck Cancers . Molecular Cancer Research . 19 . 1 . 14–24 . January 2021 . 32883697 . 7840145 . 10.1158/1541-7786.MCR-20-0565 .
7. Lei H, Wang J, Hu J, Zhu Q, Wu Y . Deubiquitinases in hematological malignancies . Biomarker Research . 9 . 1 . 66 . August 2021 . 34454635 . 8401176 . 10.1186/s40364-021-00320-w . free .
8. Nagy N, Dubois A, Szell M, Rajan N . Genetic Testing in CYLD Cutaneous Syndrome: An Update . The Application of Clinical Genetics . 14 . 427–444 . 2021 . 34744449 . 8566010 . 10.2147/TACG.S288274 . free .
9. Davies HR, Hodgson K, Schwalbe E, Coxhead J, Sinclair N, Zou X, Cockell S, Husain A, Nik-Zainal S, Rajan N . Epigenetic modifiers DNMT3A and BCOR are recurrently mutated in CYLD cutaneous syndrome . Nature Communications . 10 . 1 . 4717 . October 2019 . 31624251 . 6797807 . 10.1038/s41467-019-12746-w . 2019NatCo..10.4717D .