A5000794169- RNA Research and Splicing
- RNA modifications and cancer
- Neurogenetic and Muscular Disorders Research
- Amyotrophic Lateral Sclerosis Research
- RNA regulation and disease
- Nuclear Structure and Function
- Extracellular vesicles in disease
- Macrophage Migration Inhibitory Factor
- Doctoral Education Challenges and Solutions
- Cancer-related molecular mechanisms research
- Genetics, Bioinformatics, and Biomedical Research
- RNA and protein synthesis mechanisms
- Neuroinflammation and Neurodegeneration Mechanisms
- Hepatitis B Virus Studies
- RNA Interference and Gene Delivery
- Health Sciences Research and Education
Harvard University
2015-2023
Boston VA Research Institute
2023
University of Chinese Academy of Sciences
2017-2019
Center for Excellence in Molecular Cell Science
2017-2019
MRC Laboratory of Molecular Biology
2012-2014
The mRNA export complex TREX (TREX) is known to contain Aly, UAP56, Tex1 and the THO complex, among which UAP56 required for assembly. Here, we systematically investigated role of each human component in assembly its association with mRNA. We found that essentially a subunit complex. are all TREX, Aly directly interacts subunits Thoc2 Thoc5. Both function linking cap-binding protein CBP80. Interestingly, spliced mRNA, but not pre-mRNA, requires THO. Unexpectedly, require other associate...
Mutations in FUS cause amyotrophic lateral sclerosis (ALS), but the molecular pathways leading to neurodegeneration remain obscure. We previously found that U1 snRNP is most abundant interactor. Here, we report components of core particle (Sm proteins and snRNA), not mature snRNP-specific (U1-70K, U1A U1C), co-mislocalize with cytoplasm ALS patient fibroblasts harboring mutations nuclear localization signal (NLS). Similar results were obtained HeLa cells expressing ALS-causing R495X NLS...
Mutations in multiple RNA/DNA binding proteins cause Amyotrophic Lateral Sclerosis (ALS). Included among these are the three members of FET family (FUS, EWSR1 and TAF15) structurally similar MATR3. Here, we characterized interactomes four proteins, revealing that they largely have unique interactors, but share common an association with U1 snRNP. The latter observation led us to analyze interactome snRNP machinery. Surprisingly, this analysis revealed contains ~220 components, these, >200...
The exosome functions in the degradation of diverse RNA species, yet how it is negatively regulated remains largely unknown. Here, we show that NRDE2 forms a 1:1 complex with MTR4, nuclear cofactor critical for recruitment, via conserved MTR4-interacting domain (MID). Unexpectedly, mainly localizes speckles, where inhibits MTR4 recruitment and degradation, thereby ensures efficient mRNA export. Structural biochemical data revealed interacts MTR4's key residues, locks closed conformation,...
Viral RNA elements that facilitate mRNA export are useful tools for identifying cellular factors. Here we show hepatitis B virus post-transcriptional element (PRE) is one such element, and using PRE several new factors were identified. We found drastically enhances the cytoplasmic accumulation of cDNA transcripts independent any viral protein. Systematic deletion analysis revealed existence a 116 nt functional Sub-Element (SEP1). The RNP forms on SEP1 was affinity purified, in which TREX...
Understanding the molecular pathways disrupted in motor neuron diseases is urgently needed. Here, we employed CRISPR knockout (KO) to investigate functions of four ALS-causative RNA/DNA binding proteins (FUS, EWSR1, TAF15 and MATR3) within RNAP II/U1 snRNP machinery. We found that each these structurally related has distinct roles with FUS KO resulting loss U1 SMN complex, EWSR1 causing dissociation tRNA ligase transcription factors P-TEFb TFIIF. However, all are required for association...
A significant fraction of mRNAs are degraded by the nuclear exosome in normal cells. Here, we studied where and when these target sorted away from properly exported ones We show that upon inactivation, polyA RNAs apparently accumulated foci distinct speckles (NSs), provide several lines evidence supporting mainly correspond to accumulating mRNAs. These results suggest exosomal mRNA degradation mostly occurs outside NSs. In support this possibility, targeting NSs stabilizes them preventing...
Significance To ensure efficient and accurate gene expression, pre-mRNA processing mRNA export need to be balanced. SF3b is a core component of U2 snRNP that participates in splicing 3′ pre-mRNAs. Here, we uncovered role promoting by directly binding with the mature recruiting key adaptor THO. Intriguingly, this not dependent on snRNP, but rather enhanced upon disruption as result SF3b–THO interaction recruitment mRNA. Together, our work uncovers an important suggests competition between...
Mutations in RNA/DNA-binding proteins cause amyotrophic lateral sclerosis (ALS), but the underlying disease mechanisms remain unclear. Here, we report that a set of ALS-associated proteins, namely FUS, EWSR1, TAF15, and MATR3, impact expression genes encoding major histocompatibility complex II (MHC II) antigen presentation pathway. Both subunits MHC heterodimer, HLA-DR, are down-regulated ALS gene knockouts/knockdown HeLa human microglial cells, due to loss transcription factor CIITA....
Abstract Mutation of the essential splicing factor SF3B1 is primarily associated with hematological cancers but also occurs in solid tumors. We edited most common mutation, K700E, into human embryonic stem (ES) cells to determine effects this mutation alone an undifferentiated/non-cancer background. Unexpectedly, >20% significantly upregulated genes K700E ES lines have immune functions. Thus, may additional role proper expression appropriate cell types. In striking contrast, we found that...
Abstract Here we report that the major histocompatibility complex II (MHC II) antigen presentation pathway is regulated by ALS-causative genes, FUS, TAF15, or MATR3. Of >6000 proteins detected quantitative mass spectrometry, subunits of MHC heterodimer, HLA-DR, were top 2 downregulated in HeLa knock outs (KO) these ALS but not related gene, EWSR1. Moreover, CD74, which 3 rd essential component was KOs. We show downregulations are due to loss CIITA, a transcription factor dedicated...