TY - JOUR
T1 - Spliceostatin A interaction with SF3B limits U1 snRNP availability and causes premature cleavage and polyadenylation
AU - Yoshimoto, Rei
AU - Chhipi-Shrestha, Jagat K.
AU - Schneider-Poetsch, Tilman
AU - Furuno, Masaaki
AU - Burroughs, A. Maxwell
AU - Noma, Shohei
AU - Suzuki, Harukazu
AU - Hayashizaki, Yoshihide
AU - Mayeda, Akila
AU - Nakagawa, Shinichi
AU - Kaida, Daisuke
AU - Iwasaki, Shintaro
AU - Yoshida, Minoru
N1 - Funding Information:
We thank all the members of the Yoshida and Iwasaki laboratories for constructive discussions and technical assistance. M.Y. was supported in part by a Grant-in-Aid for Scientific Research (S) ( JP19H05640 ) from the Japan Society for the Promotion of Science (JSPS) and a Grant-in-Aid for Scientific Research on Innovative Areas ( JP18H05503 ) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT). S.I. was supported by a Grant-in-Aid for Young Scientists (A) ( JP17H04998 ) and Challenging Research (Exploratory) ( JP19K22406 ) from JSPS , a Grant-in-Aid for Transformative Research Areas (B) “Parametric Translation” ( JP20H05784 ) from MEXT , AMED-CREST ( JP20gm1410001 ) from the Japan Agency for Medical Research and Development (AMED), the Pioneering Projects (“Cellular Evolution”) and the Aging Project from RIKEN , and Takeda Science Foundation . R.Y. was supported by a Research Grant from the Hori Sciences and Arts Foundation , a Research Grant from the Nitto Foundation , a Science Research Promotion Fund from the Promotion and Mutual Aid Corporation for Private Schools of Japan ( PMAC ), and a Grants-in-Aid for Scientific Research (C) ( JP18K05563 ) from JSPS . J.K.C.S. was supported by a Grant-in-Aid for Early-Career Scientists ( JP20K15420 ) from JSPS . A.M.B. is supported by the Intramural Research Program of the National Library of Medicine, National Institutes of Health . DNA libraries were sequenced by the Vincent J. Coates Genomics Sequencing Laboratory at UC Berkeley, supported by NIH S10 OD018174 Instrumentation Grant. Computations were supported by Manabu Ishii, Itoshi Nikaido, and the Bioinformatics Analysis Environment Service on RIKEN Cloud at RIKEN Advance Center. J.K.C.S. was a recipient of a Japanese Government MEXT Scholarship.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/9/16
Y1 - 2021/9/16
N2 - RNA splicing, a highly conserved process in eukaryotic gene expression, is seen as a promising target for anticancer agents. Splicing is associated with other RNA processing steps, such as transcription and nuclear export; however, our understanding of the interaction between splicing and other RNA regulatory mechanisms remains incomplete. Moreover, the impact of chemical splicing inhibition on long non-coding RNAs (lncRNAs) has been poorly understood. Here, we demonstrate that spliceostatin A (SSA), a chemical splicing modulator that binds to the SF3B subcomplex of the U2 small nuclear ribonucleoprotein particle (snRNP), limits U1 snRNP availability in splicing, resulting in premature cleavage and polyadenylation of MALAT1, a nuclear lncRNA, as well as protein-coding mRNAs. Therefore, truncated transcripts are exported into the cytoplasm and translated, resulting in aberrant protein products. Our work demonstrates that active recycling of the splicing machinery maintains homeostasis of RNA processing beyond intron excision.
AB - RNA splicing, a highly conserved process in eukaryotic gene expression, is seen as a promising target for anticancer agents. Splicing is associated with other RNA processing steps, such as transcription and nuclear export; however, our understanding of the interaction between splicing and other RNA regulatory mechanisms remains incomplete. Moreover, the impact of chemical splicing inhibition on long non-coding RNAs (lncRNAs) has been poorly understood. Here, we demonstrate that spliceostatin A (SSA), a chemical splicing modulator that binds to the SF3B subcomplex of the U2 small nuclear ribonucleoprotein particle (snRNP), limits U1 snRNP availability in splicing, resulting in premature cleavage and polyadenylation of MALAT1, a nuclear lncRNA, as well as protein-coding mRNAs. Therefore, truncated transcripts are exported into the cytoplasm and translated, resulting in aberrant protein products. Our work demonstrates that active recycling of the splicing machinery maintains homeostasis of RNA processing beyond intron excision.
UR - http://www.scopus.com/inward/record.url?scp=85105009174&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85105009174&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2021.03.002
DO - 10.1016/j.chembiol.2021.03.002
M3 - Article
C2 - 33784500
AN - SCOPUS:85105009174
SN - 2451-9456
VL - 28
SP - 1356-1365.e4
JO - Cell Chemical Biology
JF - Cell Chemical Biology
IS - 9
ER -