RAN轉譯：修订间差异

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2021年5月1日 (六) 04:43的版本

RAN轉譯全稱為重複區關聯的非AUG轉譯（Repeat Associated Non-AUG translation），是真核生物細胞中一種異常的mRNA 轉譯機制，發生在具簡單重複序列（微衛星）的mRNA上，不需起始密碼子AUG即可轉譯重複序列，產生由一或兩種胺基酸組成的重複蛋白。亨丁頓舞蹈症與肌萎缩性脊髓侧索硬化症等數種神經退化性疾病患者基因中皆有三核苷酸重复序列扩增，因而在神經組織中由RAN轉譯生成重複蛋白，可能與及致病機制有關。目前對RAN轉譯的詳細過程與調控尚不清楚。

機制

RAN轉譯最早於2011年在第八型小腦萎縮症（SCA8）與第一型強直性肌肉失養症（DM1）患者中發現^[1]^[2]。絕大多數的mRNA轉譯是始於起始密碼子AUG，其中多數依賴5′端帽（少數病毒mRNA則是使用內部核糖體進入位點），eIF4F複合體與mRNA的5′端帽結合，核糖體小次單元（英语：Eukaryotic small ribosomal subunit (40S)）和起始tRNA及eIF1等蛋白組成43S前起始複合物，並從mRNA的5′往3′掃描，直到發現AUG後開始轉譯^[3]。RAN轉譯則發生在部分具有簡單重複序列（微衛星）的mRNA，可能也是採用類似的5′往3′核糖體掃描機制，但不需AUG作為起始密碼子，可能自重複序列上游近似AUG的密碼子（如CUG）起始，也可能自重複序列開始轉譯^[4]，通常沒有固定的開放閱讀框，可產生多種可能對細胞具毒性的二肽重复蛋白（DPR）^[5]。簡單重複序列可能位於mRNA的5′非轉譯區、編碼區或內含子中^[6]，有些案例中與基因互補的另一股DNA也會被轉錄成mRNA（反義mRNA），且兩者的重複序列均能以所有開放閱讀框進行RAN轉譯，因此最多能產生6種重複蛋白^[7]。

許多神經退化性疾病與基因中微衛星序列重複數異常有關，通稱三核苷酸重复序列疾病（英语：trinucleotide repeat disorder），過去多認為此突變表現的RNA或蛋白為致病主因，目前有觀點認為RAN轉譯可能為這些疾病的致病機制之一^[4]，但也有研究結果不支持此結論^[8]。RAN轉譯的詳細機制有待更多研究闡明，尚不清楚此過程較近似一般的5′端帽依賴型轉譯或內部核糖體進入位點依賴型轉譯，有證據顯示此過程需5′端帽，也有證據顯示其起始和重複序列形成的二級結構有關^[6]。RAN轉譯也受到一些細胞反應調控，例如整合应激反应（英语：integrated stress response）時會抑制轉譯，但可能促進RAN轉譯的進行^[4]；另外有研究發現核糖體蛋白RPS25（英语：RPS25）對RAN轉譯相當重要^[9]。目前對RAN轉譯的了解大多侷限於其在神經退化性疾病中扮演的角色，對正常狀態下（序列重複數正常的基因中）的RAN轉譯了解甚少，有研究結果顯示FMR1（英语：FMR1）基因中的RAN轉譯可抑制正常FMR1蛋白（FMRP）的表現，因而有類似上游開放閱讀框（英语：Upstream open reading frame）（uORF）的功能^[10]。

案例

RAN轉譯已在數種神經退化性疾病患者中發現，包括第八型小腦萎縮症（SCA8）患者ATXN8（英语：Twinkle (protein)）基因的CAG重複與ATXN8OS（英语：ATXN8OS）基因的CTG重複、第31型小腦萎縮症（SCA31）患者BEAN基因的TGGAA重複與SCA31-AS基因的TTCCA重複、額顳葉失智症（FTD）與肌萎缩性脊髓侧索硬化症（ALS）C9ORF72（英语：C9ORF72）基因的GGGGCC重複與C9orf72-AS基因的GGCCCC重複、第一型強直性肌肉失養症（DM1）患者DMPK（英语：Myotonin-protein kinase）基因的CTG重複與DM1-AS基因的CAG重複、第二型強直性肌肉失養症（DM2）CNBP（英语：CNBP）基因中的CCTG重複與DM2-AS基因的CAGG重複、亨丁頓舞蹈症患者Htt（英语：Huntingtin）基因的CAG重複與HD-AS基因的CTG重複、福斯氏角膜內皮失養症（英语：Fuchs endothelial corneal dystrophy）（FECD）患者TCF4（英语：TCF4）基因的CTG重複與TCF4-AS的CAG重複等^[4]。

C9ORF72

人類神經組織中表現的C9ORF72（英语：C9ORF72）基因一般有20至30個GGGGCC的短重複序列^[11]^[12] ，少數人在此位點發生突變而具有上百個短重複序列^[13] ，可能導致額顳葉失智症（FTD）或肌萎缩性脊髓侧索硬化症（ALS），其致病機制可能影響和一些蛋白（英语：RNA-binding protein）的結合能力，降低正常C9ORF72蛋白的表現量，也有觀點認為是RAN轉譯所致，此位點因開放閱讀框而異可轉譯出數種二肽重复蛋白，包括甘氨酸-丙氨酸（GA）、甘氨酸-脯氨酸（GP）、甘氨酸-精氨酸（GR）等，可能在神經元中具有毒性而致病^[14]^[15]，有約40%的FTD和約10%的ALS患者具有此突變^[16]，且與此基因互補的另一股DNA也會轉錄成mRNA並進行RAN轉譯，因此共能產生六種重複蛋白^[4]。C9ORF72進行RAN轉譯可能使用上游的CUG密碼子作為起始，此起始不只可轉譯出GA重複蛋白，還可能藉G-四聯體介導的轉譯連讀（英语：ribosome frameshifting）轉譯出GP與GR重複蛋白。另外此基因內含子中有一個上游開放閱讀框（uORF）可抑制RAN轉譯^[17]。

X染色體脆折症運動失調症候群

X染色體脆折症運動失調症候群（英语：Fragile X-associated tremor/ataxia syndrome）與FMR1（英语：FMR1）基因的CGG重複序列有關，多數人在此區域的重複少於50個，而此症病患大多有超過200個重複^[18]，且可轉譯出由甘氨酸組成的重複多肽，且其轉譯始於重複序列上游的一個特殊起始密碼子ACG^[19]^[20]。

亨丁頓舞蹈症

亨丁頓舞蹈症是Htt1基因中的CAG重複序列擴增造成，可以所有開放閱讀框進行RAN轉譯產生多麩醯胺酸、多丙氨酸和多絲氨酸三種重複蛋白，且與其互補的DNA也會轉錄成mRNA（具CUG重複序列），亦可以所有開放閱讀框進行RAN轉譯產生多白胺酸、多半胱氨酸和多丙氨酸，具突變的老鼠模型顯示這些重複蛋白在前額葉和小腦的腦區累積，可能造成神經發炎等損傷^[21]。

參考文獻

^ Zu, T.; Gibbens, B.; Doty, N. S.; Gomes-Pereira, M.; Huguet, A.; Stone, M. D.; Margolis, J.; Peterson, M.; Markowski, T. W.; Ingram, M. A. C.; Nan, Z.; Forster, C.; Low, W. C.; Schoser, B.; Somia, N. V.; Clark, H. B.; Schmechel, S.; Bitterman, P. B.; Gourdon, G.; Swanson, M. S.; Moseley, M.; Ranum, L. P. W. Non-ATG-initiated translation directed by microsatellite expansions. Proceedings of the National Academy of Sciences. 2010, 108 (1): 260–265. ISSN 0027-8424. PMC 3017129 . PMID 21173221. doi:10.1073/pnas.1013343108.
^ Copenhaver, Gregory P.; Pearson, Christopher E. Repeat Associated Non-ATG Translation Initiation: One DNA, Two Transcripts, Seven Reading Frames, Potentially Nine Toxic Entities!. PLOS Genetics. 2011, 7 (3): e1002018. ISSN 1553-7404. PMC 3053344 . PMID 21423665. doi:10.1371/journal.pgen.1002018.
^ Hershey, J.W.B. and W.C. Merrick. The pathway and mechanism of initiation of protein synthesis. N. Sonenberg, J. W. B. Hershey, M. B. Mathews (编). Translational Control of Gene Expression. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press. 2000: 185-243.
^ ^4.0 ^4.1 ^4.2 ^4.3 ^4.4 Nguyen L, Cleary JD, Ranum LPW. Repeat-Associated Non-ATG Translation: Molecular Mechanisms and Contribution to Neurological Disease.. Annu Rev Neurosci. 2019, 42: 227–247. PMC 6687071 . PMID 30909783. doi:10.1146/annurev-neuro-070918-050405.
^ Green KM, Glineburg MR, Kearse MG, Flores BN, Linsalata AE, Fedak SJ; et al. RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response.. Nat Commun. 2017, 8 (1): 2005. PMC 5722904 . PMID 29222490. doi:10.1038/s41467-017-02200-0.
^ ^6.0 ^6.1 Green KM, Linsalata AE, Todd PK. RAN translation-What makes it run?. Brain Res. 2016, 1647: 30–42. PMC 5003667 . PMID 27060770. doi:10.1016/j.brainres.2016.04.003.
^ Zu T, Liu Y, Bañez-Coronel M, Reid T, Pletnikova O, Lewis J; et al. RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia.. Proc Natl Acad Sci U S A. 2013, 110 (51): E4968–77. PMC 3870665 . PMID 24248382. doi:10.1073/pnas.1315438110.
^ Yang S, Yang H, Huang L, Chen L, Qin Z, Li S; et al. Lack of RAN-mediated toxicity in Huntington's disease knock-in mice.. Proc Natl Acad Sci U S A. 2020, 117 (8): 4411–4417. PMC 7049130 . PMID 32029588. doi:10.1073/pnas.1919197117.
^ Yamada SB, Gendron TF, Niccoli T, Genuth NR, Grosely R, Shi Y; et al. RPS25 is required for efficient RAN translation of C9orf72 and other neurodegenerative disease-associated nucleotide repeats.. Nat Neurosci. 2019, 22 (9): 1383–1388. PMC 6713615 . PMID 31358992. doi:10.1038/s41593-019-0455-7.
^ Rodriguez CM, Wright SE, Kearse MG, Haenfler JM, Flores BN, Liu Y; et al. A native function for RAN translation and CGG repeats in regulating fragile X protein synthesis.. Nat Neurosci. 2020, 23 (3): 386–397. PMC 7668390 . PMID 32066985. doi:10.1038/s41593-020-0590-1.
^ Bigio EH. C9ORF72, the new gene on the block, causes C9FTD/ALS: new insights provided by neuropathology. Acta Neuropathologica. December 2011, 122 (6): 653–5. PMC 3262229 . PMID 22101324. doi:10.1007/s00401-011-0919-7.
^ Fong JC, Karydas AM, Goldman JS. Genetic counseling for FTD/ALS caused by the C9ORF72 hexanucleotide expansion. Alzheimer's Research & Therapy. 2012, 4 (4): 27. PMC 3506941 . PMID 22808918. doi:10.1186/alzrt130.
^ Khan BK, Yokoyama JS, Takada LT, Sha SJ, Rutherford NJ, Fong JC, et al. Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion. Journal of Neurology, Neurosurgery, and Psychiatry. April 2012, 83 (4): 358–64. PMC 3388906 . PMID 22399793. doi:10.1136/jnnp-2011-301883.
^ Mori K, Weng SM, Arzberger T, May S, Rentzsch K, Kremmer E, et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science. March 2013, 339 (6125): 1335–8. Bibcode:2013Sci...339.1335M. PMID 23393093. doi:10.1126/science.1232927.
^ Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M, et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron. February 2013, 77 (4): 639–46. PMC 3593233 . PMID 23415312. doi:10.1016/j.neuron.2013.02.004.
^ Babić Leko M, Župunski V, Kirincich J, Smilović D, Hortobágyi T, Hof PR, Šimić G. C9orf72 Hexanucleotide Repeat Expansion. Behavioural Neurology. 2019, 2019: 2909168. PMC 6350563 . PMID 30774737. doi:10.1155/2019/2909168.
^ Tabet R, Schaeffer L, Freyermuth F, Jambeau M, Workman M, Lee CZ; et al. CUG initiation and frameshifting enable production of dipeptide repeat proteins from ALS/FTD C9ORF72 transcripts.. Nat Commun. 2018, 9 (1): 152. PMC 5764992 . PMID 29323119. doi:10.1038/s41467-017-02643-5.
^ Technical Standards and Guidelines for Fragile X. American College of Medical Genetics（英语：American College of Medical Genetics）. 2000-10-02 [2013-03-29].
^ Sellier C, Buijsen RAM, He F, Natla S, Jung L, Tropel P; et al. Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome.. Neuron. 2017, 93 (2): 331–347. PMC 5263258 . PMID 28065649. doi:10.1016/j.neuron.2016.12.016.
^ Gao FB, Richter JD. Microsatellite Expansion Diseases: Repeat Toxicity Found in Translation.. Neuron. 2017, 93 (2): 249–251. PMID 28103472. doi:10.1016/j.neuron.2017.01.001.
^ Tarentino AL, Maley F. A comparison of the substrate specificities of endo-beta-N-acetylglucosaminidases from Streptomyces griseus and Diplococcus Pneumoniae.. Biochem Biophys Res Commun. 1975, 67 (1): 455–62. doi:10.1016/0006-291x(75)90337-x.

[ZuGibbens2010-1] Zu, T.; Gibbens, B.; Doty, N. S.; Gomes-Pereira, M.; Huguet, A.; Stone, M. D.; Margolis, J.; Peterson, M.; Markowski, T. W.; Ingram, M. A. C.; Nan, Z.; Forster, C.; Low, W. C.; Schoser, B.; Somia, N. V.; Clark, H. B.; Schmechel, S.; Bitterman, P. B.; Gourdon, G.; Swanson, M. S.; Moseley, M.; Ranum, L. P. W. Non-ATG-initiated translation directed by microsatellite expansions. Proceedings of the National Academy of Sciences. 2010, 108 (1): 260–265. ISSN 0027-8424. PMC 3017129 . PMID 21173221. doi:10.1073/pnas.1013343108.

[CopenhaverPearson2011-2] Copenhaver, Gregory P.; Pearson, Christopher E. Repeat Associated Non-ATG Translation Initiation: One DNA, Two Transcripts, Seven Reading Frames, Potentially Nine Toxic Entities!. PLOS Genetics. 2011, 7 (3): e1002018. ISSN 1553-7404. PMC 3053344 . PMID 21423665. doi:10.1371/journal.pgen.1002018.

[3] Hershey, J.W.B. and W.C. Merrick. The pathway and mechanism of initiation of protein synthesis. N. Sonenberg, J. W. B. Hershey, M. B. Mathews (编). Translational Control of Gene Expression. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press. 2000: 185-243.

[pmid30909783-4] 4.0 ^4.1 ^4.2 ^4.3 ^4.4 Nguyen L, Cleary JD, Ranum LPW. Repeat-Associated Non-ATG Translation: Molecular Mechanisms and Contribution to Neurological Disease.. Annu Rev Neurosci. 2019, 42: 227–247. PMC 6687071 . PMID 30909783. doi:10.1146/annurev-neuro-070918-050405.

[pmid29222490-5] Green KM, Glineburg MR, Kearse MG, Flores BN, Linsalata AE, Fedak SJ; et al. RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response.. Nat Commun. 2017, 8 (1): 2005. PMC 5722904 . PMID 29222490. doi:10.1038/s41467-017-02200-0.

[pmid27060770-6] 6.0 ^6.1 Green KM, Linsalata AE, Todd PK. RAN translation-What makes it run?. Brain Res. 2016, 1647: 30–42. PMC 5003667 . PMID 27060770. doi:10.1016/j.brainres.2016.04.003.

[pmid24248382-7] Zu T, Liu Y, Bañez-Coronel M, Reid T, Pletnikova O, Lewis J; et al. RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia.. Proc Natl Acad Sci U S A. 2013, 110 (51): E4968–77. PMC 3870665 . PMID 24248382. doi:10.1073/pnas.1315438110.

[pmid32029588-8] Yang S, Yang H, Huang L, Chen L, Qin Z, Li S; et al. Lack of RAN-mediated toxicity in Huntington's disease knock-in mice.. Proc Natl Acad Sci U S A. 2020, 117 (8): 4411–4417. PMC 7049130 . PMID 32029588. doi:10.1073/pnas.1919197117.

[pmid31358992-9] Yamada SB, Gendron TF, Niccoli T, Genuth NR, Grosely R, Shi Y; et al. RPS25 is required for efficient RAN translation of C9orf72 and other neurodegenerative disease-associated nucleotide repeats.. Nat Neurosci. 2019, 22 (9): 1383–1388. PMC 6713615 . PMID 31358992. doi:10.1038/s41593-019-0455-7.

[pmid32066985-10] Rodriguez CM, Wright SE, Kearse MG, Haenfler JM, Flores BN, Liu Y; et al. A native function for RAN translation and CGG repeats in regulating fragile X protein synthesis.. Nat Neurosci. 2020, 23 (3): 386–397. PMC 7668390 . PMID 32066985. doi:10.1038/s41593-020-0590-1.

[11] Bigio EH. C9ORF72, the new gene on the block, causes C9FTD/ALS: new insights provided by neuropathology. Acta Neuropathologica. December 2011, 122 (6): 653–5. PMC 3262229 . PMID 22101324. doi:10.1007/s00401-011-0919-7.

[pmid22808918-12] Fong JC, Karydas AM, Goldman JS. Genetic counseling for FTD/ALS caused by the C9ORF72 hexanucleotide expansion. Alzheimer's Research & Therapy. 2012, 4 (4): 27. PMC 3506941 . PMID 22808918. doi:10.1186/alzrt130.

[pmid22399793-13] Khan BK, Yokoyama JS, Takada LT, Sha SJ, Rutherford NJ, Fong JC, et al. Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion. Journal of Neurology, Neurosurgery, and Psychiatry. April 2012, 83 (4): 358–64. PMC 3388906 . PMID 22399793. doi:10.1136/jnnp-2011-301883.

[14] Mori K, Weng SM, Arzberger T, May S, Rentzsch K, Kremmer E, et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science. March 2013, 339 (6125): 1335–8. Bibcode:2013Sci...339.1335M. PMID 23393093. doi:10.1126/science.1232927.

[15] Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M, et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron. February 2013, 77 (4): 639–46. PMC 3593233 . PMID 23415312. doi:10.1016/j.neuron.2013.02.004.

[Leko-16] Babić Leko M, Župunski V, Kirincich J, Smilović D, Hortobágyi T, Hof PR, Šimić G. C9orf72 Hexanucleotide Repeat Expansion. Behavioural Neurology. 2019, 2019: 2909168. PMC 6350563 . PMID 30774737. doi:10.1155/2019/2909168.

[pmid29323119-17] Tabet R, Schaeffer L, Freyermuth F, Jambeau M, Workman M, Lee CZ; et al. CUG initiation and frameshifting enable production of dipeptide repeat proteins from ALS/FTD C9ORF72 transcripts.. Nat Commun. 2018, 9 (1): 152. PMC 5764992 . PMID 29323119. doi:10.1038/s41467-017-02643-5.

[18] Technical Standards and Guidelines for Fragile X. American College of Medical Genetics（英语：American College of Medical Genetics）. 2000-10-02 [2013-03-29].

[pmid28065649-19] Sellier C, Buijsen RAM, He F, Natla S, Jung L, Tropel P; et al. Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome.. Neuron. 2017, 93 (2): 331–347. PMC 5263258 . PMID 28065649. doi:10.1016/j.neuron.2016.12.016.

[pmid28103472-20] Gao FB, Richter JD. Microsatellite Expansion Diseases: Repeat Toxicity Found in Translation.. Neuron. 2017, 93 (2): 249–251. PMID 28103472. doi:10.1016/j.neuron.2017.01.001.

[pmid0.1016/j.neuron.2015.10.038-21] Tarentino AL, Maley F. A comparison of the substrate specificities of endo-beta-N-acetylglucosaminidases from Streptomyces griseus and Diplococcus Pneumoniae.. Biochem Biophys Res Commun. 1975, 67 (1): 455–62. doi:10.1016/0006-291x(75)90337-x.

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@@ 第3行： / 第3行： @@
 }}
 [[File:Huntington's disease (5880985560).jpg|thumb|[[亨丁頓舞蹈症]]病患的{{tsl|en|Huntingtin|Htt}}基因的CAG重複數目較一般人多，可進行RAN轉譯產生致病蛋白]]
+'''RAN轉譯'''全稱為'''重複區關聯的非AUG轉譯'''（Repeat Associated Non-AUG translation），是[[真核生物]][[細胞]]中一種異常的[[mRNA]][[轉譯]]機制，發生在具[[簡單重複序列]]（微衛星）的[[mRNA]]上，不需[[起始密碼子]]AUG即可轉譯重複序列，產生由一或兩種[[胺基酸]]組成的重複蛋白。[[亨丁頓舞蹈症]]與[[肌萎缩性脊髓侧索硬化症]]等數種[[神經退化性疾病]]患者基因中皆有[[三核苷酸重复序列扩增]]，因而在神經組織中由RAN轉譯生成重複蛋白，可能與及致病機制有關。目前對RAN轉譯的詳細過程與調控尚不清楚。
-'''RAN轉譯'''全稱為'''重複區關聯的非AUG轉譯'''（Repeat Associated Non-AUG translation），是[[真核生物]][[細胞]]中一種異常的[[mRNA]][[轉譯]]機制，最早於2011年在[[小腦萎縮症|第八型小腦萎縮症]]（SCA8）與[[強直性肌肉失養症|第一型強直性肌肉失養症]]（DM1）患者中發現<ref name="ZuGibbens2010">{{cite journal|last1=Zu|first1=T.|last2=Gibbens|first2=B.|last3=Doty|first3=N. S.|last4=Gomes-Pereira|first4=M.|last5=Huguet|first5=A.|last6=Stone|first6=M. D.|last7=Margolis|first7=J.|last8=Peterson|first8=M.|last9=Markowski|first9=T. W.|last10=Ingram|first10=M. A. C.|last11=Nan|first11=Z.|last12=Forster|first12=C.|last13=Low|first13=W. C.|last14=Schoser|first14=B.|last15=Somia|first15=N. V.|last16=Clark|first16=H. B.|last17=Schmechel|first17=S.|last18=Bitterman|first18=P. B.|last19=Gourdon|first19=G.|last20=Swanson|first20=M. S.|last21=Moseley|first21=M.|last22=Ranum|first22=L. P. W.|title=Non-ATG-initiated translation directed by microsatellite expansions|journal=Proceedings of the National Academy of Sciences|volume=108|issue=1|year=2010|pages=260–265|issn=0027-8424|doi=10.1073/pnas.1013343108|pmid=21173221|pmc=3017129}}</ref><ref name="CopenhaverPearson2011">{{cite journal|last1=Copenhaver|first1=Gregory P.|last2=Pearson|first2=Christopher E.|title=Repeat Associated Non-ATG Translation Initiation: One DNA, Two Transcripts, Seven Reading Frames, Potentially Nine Toxic Entities!|journal=PLOS Genetics|volume=7|issue=3|year=2011|pages=e1002018|issn=1553-7404|doi=10.1371/journal.pgen.1002018|pmid=21423665|pmc=3053344}}</ref>。絕大多數的mRNA轉譯是始於[[起始密碼子]]AUG，其中多數依賴[[5′端帽]]（少數病毒mRNA則是使用[[內部核糖體進入位點]]），[[eIF4F]]複合體與mRNA的5′端帽結合，{{tsl|en|Eukaryotic small ribosomal subunit (40S)|40S核糖體|核糖體小次單元}}和起始[[tRNA]]及[[真核起始因子1|eIF1]]等蛋白組成{{le|43S前起始複合物|43S preinitiation complex}}，並從mRNA的5′往3′掃描，直到發現AUG後開始轉譯<ref>{{cite book|author=Hershey, J.W.B. and W.C. Merrick|chapter=The pathway and mechanism of initiation of protein synthesis|title=Translational Control of Gene Expression|editor= N. Sonenberg, J. W. B. Hershey, M. B. Mathews|year=2000|publisher= Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press|page=185-243}}</ref>。RAN轉譯可能也是採用類似的5′往3′核糖體掃描機制，但不需AUG作為起始密碼子，可能自[[三核苷酸重复序列扩增|重複序列]]上游近似AUG的密碼子（如CUG）起始，也可能自重複序列開始轉譯<ref name="pmid30909783"/>，後者通常沒有固定的[[開放閱讀框]]，可產生多種可能對細胞具毒性的二肽重复蛋白（DPR）<ref name="pmid29222490">{{cite journal| author=Green KM, Glineburg MR, Kearse MG, Flores BN, Linsalata AE, Fedak SJ | display-authors=etal| title=RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response. | journal=Nat Commun | year= 2017 | volume= 8 | issue= 1 | pages= 2005 | pmid=29222490 | doi=10.1038/s41467-017-02200-0 | pmc=5722904 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29222490  }} </ref>。有些案例中雙股DNA都會被轉錄成[[mRNA]]，且兩者的重複序列均能以所有開放閱讀框進行RAN轉譯，因此最多能產生6種重複蛋白<ref name="pmid24248382">{{cite journal| author=Zu T, Liu Y, Bañez-Coronel M, Reid T, Pletnikova O, Lewis J | display-authors=etal| title=RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. | journal=Proc Natl Acad Sci U S A | year= 2013 | volume= 110 | issue= 51 | pages= E4968-77 | pmid=24248382 | doi=10.1073/pnas.1315438110 | pmc=3870665 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24248382  }} </ref>。
+==機制==
-許多[[神經退化性疾病]]與基因中[[微衛星]]序列重複數異常有關，通稱{{le|三核苷酸重复序列疾病|trinucleotide repeat disorder}}，過去多認為此突變表現的RNA或蛋白為致病主因，目前有觀點認為RAN轉譯可能為這些疾病的致病機制之一<ref name="pmid30909783">{{cite journal| author=Nguyen L, Cleary JD, Ranum LPW| title=Repeat-Associated Non-ATG Translation: Molecular Mechanisms and Contribution to Neurological Disease. | journal=Annu Rev Neurosci | year= 2019 | volume= 42 | issue=  | pages= 227-247 | pmid=30909783 | doi=10.1146/annurev-neuro-070918-050405 | pmc=6687071 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30909783  }} </ref>，但也有研究結果不支持此結論<ref name="pmid32029588">{{cite journal| author=Yang S, Yang H, Huang L, Chen L, Qin Z, Li S | display-authors=etal| title=Lack of RAN-mediated toxicity in Huntington's disease knock-in mice. | journal=Proc Natl Acad Sci U S A | year= 2020 | volume= 117 | issue= 8 | pages= 4411-4417 | pmid=32029588 | doi=10.1073/pnas.1919197117 | pmc=7049130 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32029588  }} </ref>。RAN轉譯的詳細機制有待更多研究闡明，尚不清楚此過程較近似一般的5′端帽依賴型轉譯或內部核糖體進入位點依賴型轉譯。此過程也受到一些細胞反應調控，例如{{le|整合应激反应|integrated stress response}}時會抑制轉譯，但可能促進RAN轉譯的進行<ref name="pmid30909783"/>。目前對RAN轉譯的了解大多侷限於其在神經退化性疾病中扮演的角色，對正常狀態下（序列重複數正常的基因中）的RAN轉譯了解甚少，有研究結果顯示{{le|FMR1}}基因中的RAN轉譯可抑制正常FMR1蛋白（FMRP）的表現，因而有類似{{le|上游開放閱讀框|Upstream open reading frame}}（uORF）的功能<ref name="pmid32066985">{{cite journal| author=Rodriguez CM, Wright SE, Kearse MG, Haenfler JM, Flores BN, Liu Y | display-authors=etal| title=A native function for RAN translation and CGG repeats in regulating fragile X protein synthesis. | journal=Nat Neurosci | year= 2020 | volume= 23 | issue= 3 | pages= 386-397 | pmid=32066985 | doi=10.1038/s41593-020-0590-1 | pmc=7668390 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32066985  }} </ref>。
+RAN轉譯最早於2011年在[[小腦萎縮症|第八型小腦萎縮症]]（SCA8）與[[強直性肌肉失養症|第一型強直性肌肉失養症]]（DM1）患者中發現<ref name="ZuGibbens2010">{{cite journal|last1=Zu|first1=T.|last2=Gibbens|first2=B.|last3=Doty|first3=N. S.|last4=Gomes-Pereira|first4=M.|last5=Huguet|first5=A.|last6=Stone|first6=M. D.|last7=Margolis|first7=J.|last8=Peterson|first8=M.|last9=Markowski|first9=T. W.|last10=Ingram|first10=M. A. C.|last11=Nan|first11=Z.|last12=Forster|first12=C.|last13=Low|first13=W. C.|last14=Schoser|first14=B.|last15=Somia|first15=N. V.|last16=Clark|first16=H. B.|last17=Schmechel|first17=S.|last18=Bitterman|first18=P. B.|last19=Gourdon|first19=G.|last20=Swanson|first20=M. S.|last21=Moseley|first21=M.|last22=Ranum|first22=L. P. W.|title=Non-ATG-initiated translation directed by microsatellite expansions|journal=Proceedings of the National Academy of Sciences|volume=108|issue=1|year=2010|pages=260–265|issn=0027-8424|doi=10.1073/pnas.1013343108|pmid=21173221|pmc=3017129}}</ref><ref name="CopenhaverPearson2011">{{cite journal|last1=Copenhaver|first1=Gregory P.|last2=Pearson|first2=Christopher E.|title=Repeat Associated Non-ATG Translation Initiation: One DNA, Two Transcripts, Seven Reading Frames, Potentially Nine Toxic Entities!|journal=PLOS Genetics|volume=7|issue=3|year=2011|pages=e1002018|issn=1553-7404|doi=10.1371/journal.pgen.1002018|pmid=21423665|pmc=3053344}}</ref>。絕大多數的mRNA轉譯是始於[[起始密碼子]]AUG，其中多數依賴[[5′端帽]]（少數病毒mRNA則是使用[[內部核糖體進入位點]]），[[eIF4F]]複合體與mRNA的5′端帽結合，{{tsl|en|Eukaryotic small ribosomal subunit (40S)|40S核糖體|核糖體小次單元}}和起始[[tRNA]]及[[真核起始因子1|eIF1]]等蛋白組成{{le|43S前起始複合物|43S preinitiation complex}}，並從mRNA的5′往3′掃描，直到發現AUG後開始轉譯<ref>{{cite book|author=Hershey, J.W.B. and W.C. Merrick|chapter=The pathway and mechanism of initiation of protein synthesis|title=Translational Control of Gene Expression|editor= N. Sonenberg, J. W. B. Hershey, M. B. Mathews|year=2000|publisher= Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press|page=185-243}}</ref>。RAN轉譯則發生在部分具有[[簡單重複序列]]（微衛星）的mRNA，可能也是採用類似的5′往3′核糖體掃描機制，但不需AUG作為起始密碼子，可能自[[三核苷酸重复序列扩增|重複序列]]上游近似AUG的密碼子（如CUG）起始，也可能自重複序列開始轉譯<ref name="pmid30909783"/>，通常沒有固定的[[開放閱讀框]]，可產生多種可能對細胞具毒性的二肽重复蛋白（DPR）<ref name="pmid29222490">{{cite journal| author=Green KM, Glineburg MR, Kearse MG, Flores BN, Linsalata AE, Fedak SJ | display-authors=etal| title=RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response. | journal=Nat Commun | year= 2017 | volume= 8 | issue= 1 | pages= 2005 | pmid=29222490 | doi=10.1038/s41467-017-02200-0 | pmc=5722904 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29222490  }} </ref>。簡單重複序列可能位於mRNA的[[5′非轉譯區]]、[[編碼區]]或[[內含子]]中<ref name="pmid27060770">{{cite journal| author=Green KM, Linsalata AE, Todd PK| title=RAN translation-What makes it run? | journal=Brain Res | year= 2016 | volume= 1647 | issue=  | pages= 30-42 | pmid=27060770 | doi=10.1016/j.brainres.2016.04.003 | pmc=5003667 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27060770  }} </ref>，有些案例中與基因互補的另一股DNA也會被轉錄成[[mRNA]]（反義mRNA），且兩者的重複序列均能以所有開放閱讀框進行RAN轉譯，因此最多能產生6種重複蛋白<ref name="pmid24248382">{{cite journal| author=Zu T, Liu Y, Bañez-Coronel M, Reid T, Pletnikova O, Lewis J | display-authors=etal| title=RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. | journal=Proc Natl Acad Sci U S A | year= 2013 | volume= 110 | issue= 51 | pages= E4968-77 | pmid=24248382 | doi=10.1073/pnas.1315438110 | pmc=3870665 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24248382  }} </ref>。
+許多[[神經退化性疾病]]與基因中[[微衛星]]序列重複數異常有關，通稱{{le|三核苷酸重复序列疾病|trinucleotide repeat disorder}}，過去多認為此突變表現的RNA或蛋白為致病主因，目前有觀點認為RAN轉譯可能為這些疾病的致病機制之一<ref name="pmid30909783">{{cite journal| author=Nguyen L, Cleary JD, Ranum LPW| title=Repeat-Associated Non-ATG Translation: Molecular Mechanisms and Contribution to Neurological Disease. | journal=Annu Rev Neurosci | year= 2019 | volume= 42 | issue=  | pages= 227-247 | pmid=30909783 | doi=10.1146/annurev-neuro-070918-050405 | pmc=6687071 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30909783  }} </ref>，但也有研究結果不支持此結論<ref name="pmid32029588">{{cite journal| author=Yang S, Yang H, Huang L, Chen L, Qin Z, Li S | display-authors=etal| title=Lack of RAN-mediated toxicity in Huntington's disease knock-in mice. | journal=Proc Natl Acad Sci U S A | year= 2020 | volume= 117 | issue= 8 | pages= 4411-4417 | pmid=32029588 | doi=10.1073/pnas.1919197117 | pmc=7049130 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32029588  }} </ref>。RAN轉譯的詳細機制有待更多研究闡明，尚不清楚此過程較近似一般的5′端帽依賴型轉譯或內部核糖體進入位點依賴型轉譯，有證據顯示此過程需5′端帽，也有證據顯示其起始和重複序列形成的[[核酸二級結構|二級結構]]有關<ref name="pmid27060770"/>。RAN轉譯也受到一些細胞反應調控，例如{{le|整合应激反应|integrated stress response}}時會抑制轉譯，但可能促進RAN轉譯的進行<ref name="pmid30909783"/>；另外有研究發現[[核糖體蛋白]]{{le|RPS25}}對RAN轉譯相當重要<ref name="pmid31358992">{{cite journal| author=Yamada SB, Gendron TF, Niccoli T, Genuth NR, Grosely R, Shi Y | display-authors=etal| title=RPS25 is required for efficient RAN translation of C9orf72 and other neurodegenerative disease-associated nucleotide repeats. | journal=Nat Neurosci | year= 2019 | volume= 22 | issue= 9 | pages= 1383-1388 | pmid=31358992 | doi=10.1038/s41593-019-0455-7 | pmc=6713615 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31358992  }} </ref>。目前對RAN轉譯的了解大多侷限於其在神經退化性疾病中扮演的角色，對正常狀態下（序列重複數正常的基因中）的RAN轉譯了解甚少，有研究結果顯示{{le|FMR1}}基因中的RAN轉譯可抑制正常FMR1蛋白（FMRP）的表現，因而有類似{{le|上游開放閱讀框|Upstream open reading frame}}（uORF）的功能<ref name="pmid32066985">{{cite journal| author=Rodriguez CM, Wright SE, Kearse MG, Haenfler JM, Flores BN, Liu Y | display-authors=etal| title=A native function for RAN translation and CGG repeats in regulating fragile X protein synthesis. | journal=Nat Neurosci | year= 2020 | volume= 23 | issue= 3 | pages= 386-397 | pmid=32066985 | doi=10.1038/s41593-020-0590-1 | pmc=7668390 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32066985  }} </ref>。
 ==案例==