Restriction of an intron size en route to endothermy
Restriction of an intron size en route to endothermy
Ca2+-insensitive and-sensitive E1 subunits of the 2-oxoglutarate dehydrogenase complex (OGDHC) regulate tissue-specific NADH and ATP supply by mutually exclusive OGDH exons 4a and 4b. Here we show that their splicing is enforced by distant lariat branch points (dBPs) located near the 5′ splice site of the intervening intron. dBPs restrict the intron length and prevent transposon insertions, which can introduce or eliminate dBP competitors. The size restriction was imposed by a single dominant dBP in anamniotes that expanded into a conserved constellation of four dBP adenines in amniotes. The amniote clusters exhibit taxon-specific usage of individual dBPs, reflecting accessibility of their extended motifs within a stable RNA hairpin rather than U2 snRNA:dBP base-pairing. The dBP expansion took place in early terrestrial species and was followed by a uridine enrichment of large downstream polypyrimidine tracts in mammals. The dBP-protected megatracts permit reciprocal regulation of exon 4a and 4b by uridine-binding proteins, including TIA-1/TIAR and PUF60, which promote U1 and U2 snRNP recruitment to the 5′ splice site and BP, respectively, but do not significantly alter the relative dBP usage. We further show that codons for residues critically contributing to protein binding sites for Ca2+ and other divalent metals confer the exon inclusion order that mirrors the Irving-Williams affinity series, linking the evolution of auxiliary splicing motifs in exons to metallome constraints. Finally, we hypothesize that the dBP-driven selection for Ca2+-dependent ATP provision by E1 facilitated evolution of endothermy by optimizing the aerobic scope in target tissues.
calcium, 2-oxoglutarate dehydrogenase (OGDH), E1, enzyme, Krebs cycle, exon, intron, alternative splicing, mutually exclusive exons, lariat branch point, splicing enhancers, splicing silencers, transposon, mammalian interspersed repeat, the Irving-Williams series, metal binding site, endothermy, ectothermy, mesothermy, PUF60, TIA-1, TIAR, PTB, RBM39, RBM20, U2AF, U1 snRNP, U2 snRNP.
2460-2487
Kralovicova, Jana
b3e0c1e7-05ed-445d-b3d9-ace11e3b4878
Borovska, Ivana
d7606c38-6e5b-48f9-882e-30e213c991cd
Pengelly, Reuben
af97c0c1-b568-415c-9f59-1823b65be76d
Lee, Eunice
bd378739-961f-4b81-906a-aae1d99bb018
Abaffy, Pavel
a8c5d4cd-5bb1-4e59-93fe-87231c7b0ee7
Sindelka, Radek
f6138072-d2f5-442b-827a-38a3b0bc4408
Grutzner, Frank
69551d6a-6f7a-4311-8200-d85f86aa83ab
Vorechovsky, Igor
7245de2f-8c9b-4034-8935-9a451d9b682e
18 March 2021
Kralovicova, Jana
b3e0c1e7-05ed-445d-b3d9-ace11e3b4878
Borovska, Ivana
d7606c38-6e5b-48f9-882e-30e213c991cd
Pengelly, Reuben
af97c0c1-b568-415c-9f59-1823b65be76d
Lee, Eunice
bd378739-961f-4b81-906a-aae1d99bb018
Abaffy, Pavel
a8c5d4cd-5bb1-4e59-93fe-87231c7b0ee7
Sindelka, Radek
f6138072-d2f5-442b-827a-38a3b0bc4408
Grutzner, Frank
69551d6a-6f7a-4311-8200-d85f86aa83ab
Vorechovsky, Igor
7245de2f-8c9b-4034-8935-9a451d9b682e
Kralovicova, Jana, Borovska, Ivana, Pengelly, Reuben, Lee, Eunice, Abaffy, Pavel, Sindelka, Radek, Grutzner, Frank and Vorechovsky, Igor
(2021)
Restriction of an intron size en route to endothermy.
Nucleic Acids Research, 49 (5), .
(doi:10.1093/nar/gkab046).
Abstract
Ca2+-insensitive and-sensitive E1 subunits of the 2-oxoglutarate dehydrogenase complex (OGDHC) regulate tissue-specific NADH and ATP supply by mutually exclusive OGDH exons 4a and 4b. Here we show that their splicing is enforced by distant lariat branch points (dBPs) located near the 5′ splice site of the intervening intron. dBPs restrict the intron length and prevent transposon insertions, which can introduce or eliminate dBP competitors. The size restriction was imposed by a single dominant dBP in anamniotes that expanded into a conserved constellation of four dBP adenines in amniotes. The amniote clusters exhibit taxon-specific usage of individual dBPs, reflecting accessibility of their extended motifs within a stable RNA hairpin rather than U2 snRNA:dBP base-pairing. The dBP expansion took place in early terrestrial species and was followed by a uridine enrichment of large downstream polypyrimidine tracts in mammals. The dBP-protected megatracts permit reciprocal regulation of exon 4a and 4b by uridine-binding proteins, including TIA-1/TIAR and PUF60, which promote U1 and U2 snRNP recruitment to the 5′ splice site and BP, respectively, but do not significantly alter the relative dBP usage. We further show that codons for residues critically contributing to protein binding sites for Ca2+ and other divalent metals confer the exon inclusion order that mirrors the Irving-Williams affinity series, linking the evolution of auxiliary splicing motifs in exons to metallome constraints. Finally, we hypothesize that the dBP-driven selection for Ca2+-dependent ATP provision by E1 facilitated evolution of endothermy by optimizing the aerobic scope in target tissues.
Text
2021 Nucleic Acids Res - EN - gkab046-proofs
- Accepted Manuscript
Text
OGDH MXE SUPPLEMENT - REVISED
Spreadsheet
Table S8 - PUF60 regulated genes with known or predicted mitochondrial function
More information
Accepted/In Press date: 12 January 2021
e-pub ahead of print date: 8 February 2021
Published date: 18 March 2021
Additional Information:
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.
Keywords:
calcium, 2-oxoglutarate dehydrogenase (OGDH), E1, enzyme, Krebs cycle, exon, intron, alternative splicing, mutually exclusive exons, lariat branch point, splicing enhancers, splicing silencers, transposon, mammalian interspersed repeat, the Irving-Williams series, metal binding site, endothermy, ectothermy, mesothermy, PUF60, TIA-1, TIAR, PTB, RBM39, RBM20, U2AF, U1 snRNP, U2 snRNP.
Identifiers
Local EPrints ID: 446429
URI: http://eprints.soton.ac.uk/id/eprint/446429
ISSN: 0305-1048
PURE UUID: 4fcf36cd-faed-485d-8986-d1dae692a5fa
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Date deposited: 09 Feb 2021 17:31
Last modified: 17 Mar 2024 03:33
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Contributors
Author:
Jana Kralovicova
Author:
Ivana Borovska
Author:
Eunice Lee
Author:
Pavel Abaffy
Author:
Radek Sindelka
Author:
Frank Grutzner
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