Homozygous TAF8 mutation in a patient with intellectual disability results in undetectable TAF8 protein, but preserved RNA polymerase II transcription.
Homozygous TAF8 mutation in a patient with intellectual disability results in undetectable TAF8 protein, but preserved RNA polymerase II transcription.
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DOI：
10.1093/hmg/ddy126
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发表时间：
2018-06-15
影响因子：
3.5
通讯作者：
Tora L
中科院分区：
文献类型：
--
作者：
El-Saafin F;Curry C;Ye T;Garnier JM;Kolb-Cheynel I;Stierle M;Downer NL;Dixon MP;Negroni L;Berger I;Thomas T;Voss AK;Dobyns W;Devys D;Tora L
人通用转录因子TFIID由TBP结合蛋白（TBP）和13个TBP相关因子（TAFs）组成。在真核细胞中，TFIID被认为在所有蛋白质编码基因启动子上形成RNA聚合酶II （Pol II）起始前复合物，因此对Pol II转录至关重要。在一名患有智力残疾、轻度小头畸形、胼胝体发育不全和生长不良的儿童中，我们发现了TAF8的纯合剪接位点突变（NM_138572.2: c.781-1G > a）。我们的数据表明，患者的突变产生帧移位和不稳定的TAF8突变蛋白与不相关的c端。突变的TAF8蛋白无法在患者的成纤维细胞提取物中检测到，这表明TAF8功能丧失，突变很可能是病因。此外，我们的免疫沉淀和蛋白质组学分析表明，在患者细胞中仅存在部分TAF复合物，并且典型TFIID的形成受到损害。相反，小鼠胚胎干细胞和囊胚中TAF8的缺失会导致细胞死亡和Pol II转录的整体减少。然而，令人惊讶的是，在人类TAF8患者细胞中，我们没有检测到任何细胞表型，全基因组Pol II占用和pre-mRNA转录的显着变化。因此，必需的holo-TFIID复合物的破坏不会影响患者成纤维细胞中全局Pol II转录。我们的观察结果进一步表明，部分TAF复合物和/或含有突变TAF8的改变的TFIID可以支持人类发育，因此，缺少完整的TFIID对转录的危害比最初预测的要小。
The human general transcription factor TFIID is composed of the TATA-binding protein (TBP) and 13 TBP-associated factors (TAFs). In eukaryotic cells, TFIID is thought to nucleate RNA polymerase II (Pol II) preinitiation complex formation on all protein coding gene promoters and thus, be crucial for Pol II transcription. In a child with intellectual disability, mild microcephaly, corpus callosum agenesis and poor growth, we identified a homozygous splice-site mutation in TAF8 (NM_138572.2: c.781–1G > A). Our data indicate that the patient’s mutation generates a frame shift and an unstable TAF8 mutant protein with an unrelated C-terminus. The mutant TAF8 protein could not be detected in extracts from the patient’s fibroblasts, indicating a loss of TAF8 function and that the mutation is most likely causative. Moreover, our immunoprecipitation and proteomic analyses show that in patient cells only partial TAF complexes exist and that the formation of the canonical TFIID is impaired. In contrast, loss of TAF8 in mouse embryonic stem cells and blastocysts leads to cell death and to a global decrease in Pol II transcription. Astonishingly however, in human TAF8 patient cells, we could not detect any cellular phenotype, significant changes in genome-wide Pol II occupancy and pre-mRNA transcription. Thus, the disorganization of the essential holo-TFIID complex did not affect global Pol II transcription in the patient’s fibroblasts. Our observations further suggest that partial TAF complexes, and/or an altered TFIID containing a mutated TAF8, could support human development and thus, the absence of holo-TFIID is less deleterious for transcription than originally predicted.
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影响因子：
14.9
作者：
Deutsch EW;Csordas A;Sun Z;Jarnuczak A;Perez-Riverol Y;Ternent T;Campbell DS;Bernal-Llinares M;Okuda S;Kawano S;Moritz RL;Carver JJ;Wang M;Ishihama Y;Bandeira N;Hermjakob H;Vizcaíno JA
通讯作者：
Vizcaíno JA
影响因子：
16.6
作者：
Fournier, Marjorie;Orpinell, Meritxell;Grauffel, Cedric;Scheer, Elisabeth;Garnier, Jean-Marie;Ye, Tao;Chavant, Virginie;Joint, Mathilde;Esashi, Fumiko;Dejaegere, Annick;Gonczy, Pierre;Tora, Laszlo
通讯作者：
Tora, Laszlo
影响因子：
11.4
作者：
Brand, M;Moggs, JG;Tora, L
通讯作者：
Tora, L
DOI：
10.1073/pnas.0509063102
发表时间：
2005-12-13
影响因子：
11.1
作者：
Lebedeva, LA;Nabirochkina, EN;Tora, L
通讯作者：
Tora, L
影响因子：
16
作者：
Guermah, M;Ge, K;Roeder, RG
通讯作者：
Roeder, RG