Taspase1-dependent TFIIA cleavage coordinates head morphogenesis by limiting Cdkn2a locus transcription

Takeda, Shugaku; Sasagawa, Satoru; Oyama, Toshinao; Searleman, Adam C.; Westergard, Todd D.; Cheng, Emily H.; Hsieh, James J.

doi:10.1172/jci77075

Cited by 23 publications

(35 citation statements)

References 60 publications

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“…The amino acid residue p.Thr234 of TASP1 is highly conserved during evolution and the p.Thr234Met missense variant was found consistently to be disease‐causing or damaging by multiple in silico prediction tools. Furthermore, the p.Thr234 residue is the active‐site nucleophile to proteolyze polypeptide substrates (Takeda et al, ). In addition, the substitution of p.Thr234 with Alanine has already been shown in vitro to render TASP1 inactive (Hsieh et al, ).…”

Section: Clinical Features Of the Reported Childrenmentioning

confidence: 99%

Homozygous loss‐of‐function variants of TASP1 , a gene encoding an activator of the histone methyltransferases KMT2A and KMT2D, cause a syndrome of developmental delay, happy demeanor, distinctive facial features, and congenital anomalies

Suleiman

Riedhammer

Jicinsky³

et al. 2019

Human Mutation

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We report four unrelated children with homozygous loss‐of‐function variants in TASP1 and an overlapping phenotype comprising developmental delay with hypotonia and microcephaly, feeding difficulties with failure‐to‐thrive, recurrent respiratory infections, cardiovascular malformations, cryptorchidism, happy demeanor, and distinctive facial features. Two children had a homozygous founder deletion encompassing exons 5–11 of TASP1, the third had a homozygous missense variant, c.701 C>T (p.Thr234Met), affecting the active site of the encoded enzyme, and the fourth had a homozygous nonsense variant, c.199 C>T (p.Arg67*). TASP1 encodes taspase 1 (TASP1), which is responsible for cleaving, thus activating, the lysine methyltransferases KMT2A and KMT2D, which are essential for histone methylation and transcription regulation. The consistency of the phenotype, the critical biological function of TASP1, the deleterious nature of the TASP1 variants, and the overlapping features with Wiedemann–Steiner and Kabuki syndromes respectively caused by pathogenic variants in KMT2A and KMT2D all support that TASP1 is a disease‐related gene.

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Section: Clinical Features Of the Reported Childrenmentioning

confidence: 99%

Homozygous loss‐of‐function variants of TASP1 , a gene encoding an activator of the histone methyltransferases KMT2A and KMT2D, cause a syndrome of developmental delay, happy demeanor, distinctive facial features, and congenital anomalies

Suleiman

Riedhammer

Jicinsky³

et al. 2019

Human Mutation

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“…It became obvious that the uncleaved form of TFIIA is also transcriptionally active in early embryogenesis and sufficient for bulk transcription (50). Nevertheless, cleavage of TFIIA by threonine aspartase 1 is consistently described as a regulatory mechanism to fine‐tune the activity of different promoter complexes (48, 49, 51, 52). In doing so, cleaved TFIIA executes activating as well as repressing functions.…”

Section: Natural Substrates Of Threonine Aspartasementioning

confidence: 99%

“…A recent study demonstrated that threonine aspartase 1‐mediated cleavage of TFIIA ensures proper head formation during mouse development (52). In this mouse model, threonine aspartase 1 deficiency led to craniofacial malformations and high lethality within the first days after birth (Fig.…”

Section: The Relevance Of Threonine Aspartase 1 For Development and Cmentioning

confidence: 99%

“…3 ). The authors could show that disruption of proliferation accounts for the abnormal development of the Tasp –/– prosencephalon, which in turn was explained by disruption of normal CDKI protein expression (52). Thus, suppression of 2 CDKIs from the Cdkn2a locus, p16Ink4a, and p19Arf, during cranial morphogenesis, is crucial for normal head development.…”

Section: The Relevance Of Threonine Aspartase 1 For Development and Cmentioning

confidence: 99%

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Cleaving for growth: threonine aspartase 1—a protease relevant for development and disease

et al. 2015

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“…The precursor of TFIIAα/β can be digested by taspase1, but uncleaved TFIIAα/β remains active in transcriptional regulation (20). Recent studies showed that the cleavage of TFIIA by taspase 1 is involved in a number of molecular and biological processes (21)(22)(23)(24). Although TFIIA was originally characterized as a general transcription factor, TFIIA is dispensable in transcription in vitro (25)(26); perhaps, TFIIA is better to be described as a general cofactor because it acts as an anti-repressor or coactivator in transcriptional regulation (27-31).…”

mentioning

confidence: 99%

A transcription factor IIA-binding site differentially regulates RNA polymerase II-mediated transcription in a promoter context-dependent manner

Wang

Zhao

et al. 2017

Journal of Biological Chemistry

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/pure/about/ebr-terms Eukaryotic transcription initiation by RNA polymerase II requires numerous transcription factors and cofactors to nucleate at core promoter to form a pre-initiation complex (1, 2). The core promoter plays a critical role during transcriptional initiation and contains a number of DNA sequence elements such as the TATA box, the initiator, the downstream promoter element, the TFIIB recognition elements (BREs) and others (1-4). These elements are recognized by general transcription factors and cofactors (5-9), and assist to direct and orientate pre-initiation complex formation at the promoter. Core promoter elements not only regulate the activity of transcription but also determine transcription start site selection (4, 10 and 11). Genome-wide studies have revealed that many genes lack so-called 'canonical' core promoter elements, suggesting that other core promoter elements remain to be discovered. Indeed, a recent study showed that core promoter element, DTIE, directs transcription start site selection of genes with TATA-less promoters (12). Nevertheless, it has been proposed that core promoter elements may not be essential to transcription of some genes in vivo (13), suggesting that canonical core promoter elements fine-tune physiological responses for specific genes (4). It has been shown that many 'noncanonical' promoters instead contain epigenetic marks including histone modifications (H3K4me3 and H3K27me3) and DNA marks such as enhancers, CpG islands and ATG deserts (14-16). The mechanisms by which canonical or noncanonical core promoters regulate transcriptional initiation is not fully understood.Transcription factor TFIIA comprises of three subunits, α, β and γ; TFIIAα/β and TFIIAγ are encoded by different genes (17-19). The precursor of TFIIAα/β can be digested by taspase1, but uncleaved TFIIAα/β remains active in transcriptional regulation (20). Recent studies showed that the cleavage of TFIIA by taspase 1 is involved in a number of molecular and biological processes (21-24). Although TFIIA was originally characterized as a general transcription factor, TFIIA is dispensable in transcription in vitro (25-26); perhaps, TFIIA is better to be described as a general cofactor because it acts as an anti-repressor or coactivator in transcriptional regulation (27)(28)(29)(30)(31). TFIIA can counteract the inhibitory roles of TAF1 and BTAF1 during TBP binding to the TATA box as well as the repressive effects of NC2 and HMGB1 on transcription (27, 28). TFIIA has also been shown to stabilize TFIID binding to DNA by interacting with transcriptional activators, TBP-associated factors (29, 30,(32)(33)(34) and TBP-related factors (35-37). It has been proposed that TFIIA induces the disassociation of TBP dimers and promotes the association between TBP and the TATA-box promoter (38). TFIIA stabil...

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Taspase1-dependent TFIIA cleavage coordinates head morphogenesis by limiting Cdkn2a locus transcription

Cited by 23 publications

References 60 publications

Homozygous loss‐of‐function variants of TASP1 , a gene encoding an activator of the histone methyltransferases KMT2A and KMT2D, cause a syndrome of developmental delay, happy demeanor, distinctive facial features, and congenital anomalies

Homozygous loss‐of‐function variants of TASP1 , a gene encoding an activator of the histone methyltransferases KMT2A and KMT2D, cause a syndrome of developmental delay, happy demeanor, distinctive facial features, and congenital anomalies

Cleaving for growth: threonine aspartase 1—a protease relevant for development and disease

A transcription factor IIA-binding site differentially regulates RNA polymerase II-mediated transcription in a promoter context-dependent manner

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