TY - JOUR
T1 - Re-splicing of mature mRNA in cancer cells promotes activation of distant weak alternative splice sites
AU - Kameyama, Toshiki
AU - Suzuki, Hitoshi
AU - Mayeda, Akila
N1 - Funding Information:
Grants-in-Aid for Challenging Exploratory Research, Japan Society for the Promotion of Science (JSPS) [21657033 and 23651198 to T.K., 20651051 to A.M.]; Grant-in-Aid for Scientific Research on Innovative Areas ‘Diversity and asymmetry achieved by RNA program’, Japan Ministry of Education, Culture, Sports, Science and Technology (MEXT) [23112722 to A.M.]; Program for the Strategic Research Foundation at Private Universities, MEXT (to A.M., in part). Funding for the open access charge: Grant-in-Aid, MEXT [23112722].
PY - 2012/9
Y1 - 2012/9
N2 - Transcripts of the human tumor susceptibility gene 101 (TSG101) are aberrantly spliced in many cancers. A major aberrant splicing event on the TSG101 pre-mRNA involves joining of distant alternative 5′ and 3′ splice sites within exon 2 and exon 9, respectively, resulting in the extensive elimination of the mRNA. The estimated strengths of the alternative splice sites are much lower than those of authentic splice sites. We observed that the equivalent aberrant mRNA could be generated from an intron-less TSG101 gene expressed ectopically in breast cancer cells. Remarkably, we identified a pathway-specific endogenous lariat RNA consisting solely of exonic sequences, predicted to be generated by a re-splicing between exon 2 and exon 9 on the spliced mRNA. Our results provide evidence for a two-step splicing pathway in which the initial constitutive splicing removes all 14 authentic splice sites, thereby bringing the weak alternative splice sites into close proximity. We also demonstrate that aberrant multiple-exon skipping of the fragile histidine triad (FHIT) pre-mRNA in cancer cells occurs via re-splicing of spliced FHIT mRNA. The re-splicing of mature mRNA can potentially generate mutation-independent diversity in cancer transcriptomes. Conversely, a mechanism may exist in normal cells to prevent potentially deleterious mRNA re-splicing events.
AB - Transcripts of the human tumor susceptibility gene 101 (TSG101) are aberrantly spliced in many cancers. A major aberrant splicing event on the TSG101 pre-mRNA involves joining of distant alternative 5′ and 3′ splice sites within exon 2 and exon 9, respectively, resulting in the extensive elimination of the mRNA. The estimated strengths of the alternative splice sites are much lower than those of authentic splice sites. We observed that the equivalent aberrant mRNA could be generated from an intron-less TSG101 gene expressed ectopically in breast cancer cells. Remarkably, we identified a pathway-specific endogenous lariat RNA consisting solely of exonic sequences, predicted to be generated by a re-splicing between exon 2 and exon 9 on the spliced mRNA. Our results provide evidence for a two-step splicing pathway in which the initial constitutive splicing removes all 14 authentic splice sites, thereby bringing the weak alternative splice sites into close proximity. We also demonstrate that aberrant multiple-exon skipping of the fragile histidine triad (FHIT) pre-mRNA in cancer cells occurs via re-splicing of spliced FHIT mRNA. The re-splicing of mature mRNA can potentially generate mutation-independent diversity in cancer transcriptomes. Conversely, a mechanism may exist in normal cells to prevent potentially deleterious mRNA re-splicing events.
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U2 - 10.1093/nar/gks520
DO - 10.1093/nar/gks520
M3 - Article
C2 - 22675076
AN - SCOPUS:84870561895
SN - 0305-1048
VL - 40
SP - 7896
EP - 7906
JO - Nucleic acids research
JF - Nucleic acids research
IS - 16
ER -