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Short cryptic exons mediate recursive splicing in Drosophila.

Nat Struct Mol Biol. 2018 May;25(5):365-371. Epub 2018 Apr 09
Brian Joseph 1 , Shu Kondo 2 , Eric C Lai 3
Brian Joseph 1 , Shu Kondo 2 , Eric C Lai 3

[No authors listed]

Author information
  • 1 Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 2 Invertebrate Genetics Laboratory, National Institute of Genetics, Mishima, Japan.
  • 3 Department of Developmental Biology, Sloan-Kettering Institute, New York, NY, USA. laie@mskcc.org.

摘要


Many long Drosophila introns are processed by an unusual recursive strategy. The presence of ~200 adjacent splice acceptor and splice donor sites, termed ratchet points (RPs), were inferred to reflect 'zero-nucleotide exons', whose sequential processing subdivides removal of long host introns. We used CRISPR-Cas9 to disrupt several intronic RPs in Drosophila melanogaster, some of which recapitulated characteristic loss-of-function phenotypes. Unexpectedly, selective disruption of RP splice donors revealed constitutive retention of unannotated short exons. Assays using functional minigenes confirm that unannotated cryptic splice donor sites are critical for recognition of intronic RPs, demonstrating that recursive splicing involves the recognition of cryptic RP exons. This appears to be a general mechanism, because canonical, conserved splice donors are specifically enriched in a 40-80-nt window downstream of known and newly annotated intronic RPs and exhibit similar properties to a broadly expanded class of expressed RP exons. Overall, these studies unify the mechanism of Drosophila recursive splicing with that in mammals.