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PreprintCited by 5RNA Research and SplicingRNA and protein synthesis mechanismsNuclear Structure and Function

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Selected humanization of yeast U1 snRNP leads to global suppression of pre-mRNA splicing and mitochondrial dysfunction in the budding yeast

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Chalivendra, Subbaiah, Shi, Shasha, Li, Xueni, Kuang, Zhiling, Giovinazzo, Joseph, Zhang, Lingdi, Rossi, John, Saviola, Anthony J., Wang, Jingxin, Welty, Robb, Liu, Shiheng, Vaeth, Katherine, Zhou, Z. Hong, Hansen, Kirk C., Taliaferro, J. Matthew, Zhao, Rui·2023·RNA
DOI 10.1101/2023.12.15.571893PMC PMC11251525

Preprint — published as 10.1261/rna.079917.123 · Paper page

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Abstract

The recognition of 5’ splice site (5’ ss) is one of the earliest steps of pre-mRNA splicing. To better understand the mechanism and regulation of 5’ ss recognition, we selectively humanized components of the yeast U1 snRNP to reveal the function of these components in 5’ ss recognition and splicing. We targeted U1C and Luc7, two proteins that interact with and stabilize the yeast U1 (yU1) snRNA and the 5’ ss RNA duplex. We replaced the Zinc-Finger (ZnF) domain of yU1C with its human counterpart, which resulted in cold-sensitive growth phenotype and moderate splicing defects. Next, we added an auxin-inducible degron to yLuc7 protein and found that Luc7-depleted yU1 snRNP resulted in the concomitant loss of PRP40 and Snu71 (two other essential yeast U1 snRNP proteins), and further biochemical analyses suggest a model of how these three proteins interact with each other in the U1 snRNP. The loss of these proteins resulted in a significant growth retardation accompanied by a global suppression of pre-mRNA splicing. The splicing suppression led to mitochondrial dysfunction as revealed by a release of Fe 2+ into the growth medium and an induction of mitochondrial reactive oxygen species. Together, these observations indicate that the human U1C ZnF can substitute that of yeast, Luc7 is essential for the incorporation of the Luc7-Prp40-Snu71 trimer into yeast U1 snRNP, and splicing plays a major role in the regulation of mitochondria function in yeast.

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Metadata

Authors
Chalivendra, S., Shi, S., Li, X., Kuang, Z., Giovinazzo, J., Zhang, L., Rossi, J., Saviola, A. J., Wang, J., Welty, R., Liu, S., Vaeth, K., Zhou, Z. H., Hansen, K. C., Taliaferro, J. M., & Zhao, R.
Affiliations
  • University of Colorado Anschutz (US)
  • University of Kansas (US)
  • University of California, Los Angeles (US)
Corresponding author
Zhao, Rui
ORCID
Venue
RNA
Publisher
openRxiv
Published
2023-12-15
Volume
30
Issue
8
Pages
1070-1088
ISSN
1355-8382 (ISSN-L)
DOI
10.1101/2023.12.15.571893
PMC
PMC11251525
OpenAlex
W4396509041
Cited by
5
References
1
Citations by year
2026: 1 · 2025: 2 · 2024: 2
FWCI
0.67
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • RNA (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • U.S. Department of Energy
  • Oregon Health and Science University
  • National Institutes of Health (T32CA17468)
  • Office of Science
  • Weill Cornell Medical College
  • University of California, San Francisco (P41-GM103311)
  • Cancer Center, University of Colorado (P30 CA046934)
  • Anschutz Medical Campus, University of Colorado (P30CA046934)
  • National Cancer Institute (T32CA174648, P30CA046934)
  • National Institute of General Medical Sciences (GM103311, P41GM103311, R01GM126157, U24GM129547, R35GM133385, R35GM145289, R01GM071940, R01GM129325, R35GM147498)
  • Biological and Environmental Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
Keywords
U1 snRNP, pre-mRNA splicing, 5' splice site recognition, auxin-inducible degron, mitochondrial dysfunction, reactive oxygen species, iron release

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