ACD (gene) explained

Adrenocortical dysplasia protein homolog is a protein that in humans is encoded by the ACD gene.^{[1] [2] [3]}

Function

This gene encodes a protein that is involved in telomere function. This protein is one of six core proteins in the telosome/shelterin telomeric complex, which functions to maintain telomere length and to protect telomere ends. Through its interaction with other components, this protein plays a key role in the assembly and stabilization of this complex, and it mediates the access of telomerase to the telomere. Multiple transcript variants encoding different isoforms have been found for this gene. This gene, which is also referred to as TPP1, is distinct from the unrelated TPP1 gene on chromosome 11, which encodes tripeptidyl-peptidase I.^[3]

TPP1 is a component of the telomere-specific shelterin complex, which facilitates the replication of the double-stranded telomeric DNA tracts and protects the telomeric end from unregulated DNA repair activities. TPP1 mainly functions as a regulator of telomerase recruitment, activation, and regulation.^[4] Although TPP1 was originally described as a bridging factor between TRF1 and TRF2, which participate in a pathway with POT1 as a negative regulator of telomerase-dependent telomere length control,^[5] more recent studies suggest that TPP1 could directly promotes telomerase activity at the telomere.^[6] TPP1 is both necessary and sufficient to recruit the telomerase enzyme to telomeres, and is the only shelterin protein in direct contact with telomerase.^[7]

A part of the TPP1 oligonucleotide/oligosaccharide-binding (OB) fold named TEL patch that interacts with the catalytic subunit of telomerase, hTERT, has been proven essential for telomerase activation.^[8] TPP1 has also been demonstrated as the only pathway required for recruitment of telomerase to chromosome ends, and it also defines telomere length homeostasis in hESCs.

Interactions

ACD (gene) has been shown to interact with POT1^[9] and TINF2.^{[1] [2]}

• POT1 ^[10]
• hTERT ^{[6] [5]}
• TIN2^[11]
• TRF1
• TRF2
• Telomerase^[12]

External links

• • • PDBe-KB provides an overview of all the structure information available in the PDB for Human Adrenocortical dysplasia protein homolog

Further reading

• de Lange T . Shelterin: the protein complex that shapes and safeguards human telomeres. . Genes Dev. . 19 . 18 . 2100–10 . 2005 . 16166375 . 10.1101/gad.1346005 . free .
• Songyang Z, Liu D . Inside the mammalian telomere interactome: regulation and regulatory activities of telomeres. . Crit. Rev. Eukaryot. Gene Expr. . 16 . 2 . 103–18 . 2006 . 16749892 . 10.1615/critreveukargeneexpr.v16.i2.10 .
• Cristofari G, Sikora K, Lingner J . Telomerase unplugged. . ACS Chem. Biol. . 2 . 3 . 155–8 . 2007 . 17373762 . 10.1021/cb700037c . free .
• Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA . A "double adaptor" method for improved shotgun library construction. . Anal. Biochem. . 236 . 1 . 107–13 . 1996 . 8619474 . 10.1006/abio.1996.0138 .
• Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA . Large-scale concatenation cDNA sequencing. . Genome Res. . 7 . 4 . 353–8 . 1997 . 9110174 . 139146 . 10.1101/gr.7.4.353 .
• Houghtaling BR, Cuttonaro L, Chang W, Smith S . A dynamic molecular link between the telomere length regulator TRF1 and the chromosome end protector TRF2. . Curr. Biol. . 14 . 18 . 1621–31 . 2005 . 15380063 . 10.1016/j.cub.2004.08.052 . 19036934 . free .
• Keegan CE, Hutz JE, Else T, Adamska M, Shah SP, Kent AE, Howes JM, Beamer WG, Hammer GD . Urogenital and caudal dysgenesis in adrenocortical dysplasia (acd) mice is caused by a splicing mutation in a novel telomeric regulator. . Hum. Mol. Genet. . 14 . 1 . 113–23 . 2005 . 15537664 . 10.1093/hmg/ddi011 . free .
• Hutz JE, Krause AS, Achermann JC, Vilain E, Tauber M, Lecointre C, McCabe ER, Hammer GD, Keegan CE . IMAGe association and congenital adrenal hypoplasia: no disease-causing mutations found in the ACD gene. . Mol. Genet. Metab. . 88 . 1 . 66–70 . 2006 . 16504561 . 10.1016/j.ymgme.2006.01.006 .
• Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási AL, Vidal M, Zoghbi HY . A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. . Cell . 125 . 4 . 801–14 . 2006 . 16713569 . 10.1016/j.cell.2006.03.032 . 13709685 . free .
• O'Connor MS, Safari A, Xin H, Liu D, Songyang Z . A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly. . Proc. Natl. Acad. Sci. U.S.A. . 103 . 32 . 11874–9 . 2006 . 16880378 . 1567669 . 10.1073/pnas.0605303103 . 2006PNAS..10311874O . free .
• Xin H, Liu D, Wan M, Safari A, Kim H, Sun W, O'Connor MS, Songyang Z . TPP1 is a homologue of ciliate TEBP-beta and interacts with POT1 to recruit telomerase. . Nature . 445 . 7127 . 559–62 . 2007 . 17237767 . 10.1038/nature05469 . 2007Natur.445..559X . 4347362 .
• Wang F, Podell ER, Zaug AJ, Yang Y, Baciu P, Cech TR, Lei M . The POT1-TPP1 telomere complex is a telomerase processivity factor. . Nature . 445 . 7127 . 506–10 . 2007 . 17237768 . 10.1038/nature05454 . 2007Natur.445..506W . 2027.42/62923 . 4383587 . free .
• Wang F, Podell ER, Zaug AJ, Yang Y, Baciu P, Cech TR, Lei M . The POT1-TPP1 telomere complex is a telomerase processivity factor. . Nature . 445 . 7127 . 506–10 . 2007 . 17237768 . 10.1038/nature05454 . 2007Natur.445..506W . 2027.42/62923 . 4383587 . free .

Notes and References

1. Ye JZ, Hockemeyer D, Krutchinsky AN, Loayza D, Hooper SM, Chait BT, de Lange T . POT1-interacting protein PIP1: a telomere length regulator that recruits POT1 to the TIN2/TRF1 complex . Genes Dev . 18 . 14 . 1649–54 . July 2004 . 15231715 . 478187 . 10.1101/gad.1215404 .
2. Liu D, Safari A, O'Connor MS, Chan DW, Laegeler A, Qin J, Songyang Z . PTOP interacts with POT1 and regulates its localization to telomeres . Nat Cell Biol . 6 . 7 . 673–80 . July 2004 . 15181449 . 10.1038/ncb1142 . 11543383 .
3. Web site: Entrez Gene: ACD adrenocortical dysplasia homolog (mouse).
4. September 2014. Modern genome editing meets telomeres: the many functions of TPP1. Genes & Development. 28. 17. 1857–8. 10.1101/gad.250316.114. 4197952. 25184673. Jan Karlseder. Karlseder J.
5. August 2007. Telomere protection by mammalian Pot1 requires interaction with Tpp1. Nature Structural & Molecular Biology. 14. 8. 754–61. 10.1038/nsmb1270. 17632522. Hockemeyer D, Palm W, Else T, Daniels JP, Takai KK, Ye JZ, Keegan CE, de Lange T, Hammer GD. 84294729.
6. December 2012. The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity. Nature. 492. 7428. 285–9. 10.1038/nature11648. 3521872. 23103865. Nandakumar J, Bell CF, Weidenfeld I, Zaug AJ, Leinwand LA, Cech TR. 2012Natur.492..285N.
7. Grill S, Nandakumar J . Molecular mechanisms of telomere biology disorders . . 296 . 100064 . 2021 . 10.1074/jbc.REV120.014017 . 7948428 . 33482595 . free .
8. September 2014. Genetic and molecular identification of three human TPP1 functions in telomerase action: recruitment, activation, and homeostasis set point regulation. Genes & Development. 28. 17. 1885–99. 10.1101/gad.246819.114. 4197946. 25128433. Sexton AN, Regalado SG, Lai CS, Cost GJ, O'Neil CM, Urnov FD, Gregory PD, Jaenisch R, Collins K, Hockemeyer D.
9. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . . 437 . 7062 . 1173–8 . October 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
10. January 2010. In vivo stoichiometry of shelterin components. The Journal of Biological Chemistry. 285. 2. 1457–67. 10.1074/jbc.M109.038026. 2801271. 19864690. Takai KK, Hooper S, Blackwood S, Gandhi R, de Lange T. free .
11. August 2006. A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly. Proceedings of the National Academy of Sciences of the United States of America. 103. 32. 11874–9. 10.1073/pnas.0605303103. 1567669. 16880378. O'Connor MS, Safari A, Xin H, Liu D, Songyang Z. 2006PNAS..10311874O. free.
12. March 2010. Functional interaction between telomere protein TPP1 and telomerase. Genes & Development. 24. 6. 613–22. 10.1101/gad.1881810. 2841338. 20231318. Zaug AJ, Podell ER, Nandakumar J, Cech TR.