| 2018 |
Taspase1-dependent proteolytic cleavage of MLL1 destabilizes MLL1; loss of taspase1 increases uncleaved MLL1 stability and its association with chromatin, displacing MLL chimeras in leukemic cells. Casein kinase II (CKII) phosphorylates MLL1 proximal to the taspase1 cleavage site, facilitating cleavage; pharmacological CKII inhibition blocks MLL1 processing and increases MLL1 stability. |
Genetic loss-of-function (taspase1 KO), chromatin fractionation/ChIP, pharmacological inhibition (CKII inhibitor), in vivo MLL-AF9 mouse leukemia model |
Genes & development |
High |
30573454
|
| 2014 |
Taspase1 cleaves MLL1 in vivo; this cleavage is required for MMTV-neu-driven breast tumorigenesis by enabling expression of cyclins E and A. Mice with homozygous noncleavable MLL alleles (MLL-nc/nc) are protected from HER2/neu-driven mammary tumor formation, establishing MLL as the primary Taspase1 substrate in this oncogenic axis. |
Conditional knockout mice (MMTV-neu;MMTV-cre;Tasp1(F/-)), transgenic knockin of noncleavable MLL (MLL-nc/nc), knockdown-rescue experiments in HER2+ cell lines |
Cell research |
High |
25267403
|
| 2015 |
Taspase1-mediated cleavage of TFIIA is the principal substrate event orchestrating craniofacial morphogenesis. Loss of TASP1 causes catastrophic craniofacial malformations; uncleaved TFIIA accumulates at p16Ink4a and p19Arf promoters and drives their transcription, limiting cell proliferation. Genetic reduction of Cdkn2a (especially p16Ink4a) markedly rescues craniofacial anomalies in TASP1-deficient mice. |
Genetic epistasis (Tasp1 KO × Cdkn2a KO compound mutants), knockin of noncleavable TASP1 substrates (TFIIA vs. MLL), ChIP analysis of p16/p19 promoters |
The Journal of clinical investigation |
High |
25664857
|
| 2021 |
Taspase1-mediated cleavage of TFIIAα-β (rather than MLL1 or MLL2) is required for proper fetal liver hematopoietic stem cell self-renewal/quiescence and correct segmental identities of the axial skeleton in mouse embryos. Noncleavable TFIIAα-β knockin mice displayed more pronounced fetal liver and axial skeleton defects than noncleavable MLL1 or MLL2 knockins. |
Genetic deletion (Tasp1 KO), substrate-specific noncleavable knockin mice (TFIIAα-β, MLL1, MLL2), phenotypic comparison of embryonic hematopoiesis and skeletal segmentation |
JCI insight |
High |
34156981
|
| 2020 |
TASP1 (Taspase1) cleaves REV3L, the catalytic subunit of DNA polymerase ζ, generating an N-terminal 70-kDa fragment and a C-terminal polymerase catalytic domain fragment. This proteolytic cleavage prevents ubiquitination and proteasome-mediated degradation of REV3L, thereby stabilizing it. Endogenous REV3L point mutations that compromise TASP1 cleavage markedly impair cellular responses to UV and cisplatin-induced DNA lesions. |
In vitro cleavage assay, endogenous knockin point mutations (HCT116), ubiquitination assay, DNA damage response assays (UV, cisplatin) |
Nucleic acids research |
High |
32064513
|
| 2022 |
Taspase1 (TASP1) cleaves the unconventional myosin Myo1f. Myo1f is a nucleo-cytoplasmic shuttle protein processed by nuclear Taspase1, and Myo1f promotes filopodia formation, cellular adhesion, and migration. Taspase1-mediated proteolysis of Myo1f antagonizes filopodia formation; inverse correlation between Myo1f concentration and TASP1 expression was observed in macrophages versus monocytes. |
Co-IP/pulldown to identify Myo1f as substrate, cleavage assays, live-cell imaging of filopodia, knockdown/overexpression experiments, nuclear fractionation |
iScience |
Medium |
35601920
|
| 2019 |
Homozygous loss-of-function variants in TASP1 (including active-site missense p.Thr234Met, deletion of exons 5-11, and nonsense p.Arg67*) cause a recognizable developmental syndrome. TASP1 encodes taspase1, which activates KMT2A and KMT2D (histone methyltransferases) by proteolytic cleavage. Loss of TASP1 function phenocopies aspects of Wiedemann-Steiner (KMT2A) and Kabuki (KMT2D) syndromes, consistent with TASP1 acting upstream of these methyltransferases. |
Whole-exome sequencing, active-site missense variant in patients (p.Thr234Met affects catalytic residue), clinical phenotype comparison with KMT2A/KMT2D syndrome patients |
Human mutation |
Medium |
31209944
|
| 2022 |
TASP1 deficiency leads to HOX gene downregulation (HOXA4, HOXA7, HOXA1, HOXB2) and dysregulation of transcription factor TFIIA in patient fibroblasts (by western blot, RNA-seq, and proteomics). TASP1 loss produces a distinct DNA methylation profile intermediate between control and Kabuki syndrome (KMT2D) profiles. Zebrafish tasp1 knockout caused smaller head size and abnormal cranial cartilage formation. |
Western blot (absence of TASP1 protein), RNA-seq, proteomics from patient fibroblasts, methylome analysis, zebrafish CRISPR knockout |
Human molecular genetics |
Medium |
35512351
|
| 2018 |
The C. elegans tasp-1 gene (ortholog of TASP1) modulates levels of ELT-2 protein in the early endoderm; loss of tasp-1 leads to modest increases in ELT-2 levels, consistent with a role in regulating transcription factor abundance. tasp-1 was identified as a suppressor of a lethal end-1 end-3 mutation, verified by RNAi and CRISPR/Cas9. |
Genetic suppressor screen, RNAi, CRISPR/Cas9 loss-of-function in C. elegans |
G3 (Bethesda, Md.) |
Medium |
29593072
|
| 2008 |
HNF4alpha splice variants transcriptionally regulate TASP1 expression; TASP1 is a downstream target of HNF4alpha in hepatocellular carcinoma, with induced expression in mouse and human HCCs, identified by chromatin immunoprecipitation followed by cloning/sequencing, EMSA, and qRT-PCR. |
Chromatin immunoprecipitation (ChIP), EMSA, qRT-PCR, Western blotting, immunohistochemistry |
Gastroenterology |
Medium |
18395097
|