Direct m6A recognition by IMP1 underlays an alternative model of target selection for non-canonical methyl-readers

Giancarlo Abis; Giuseppe Nicastro; Pierre Klein; Sofia Esteban-Serna; Christopher Gallagher; Belen Chaves-Arquero; Sunny Cai; Angelo Miguel Figueiredo; Stephen R Martin; Ian A. Taylor; Andres Ramos

doi:10.1093/nar/gkad534

Direct m6A recognition by IMP1 underlays an alternative model of target selection for non-canonical methyl-readers

Giancarlo Abis, Giuseppe Nicastro, Pierre Klein, Sofia Esteban-Serna, Christopher Gallagher, Belen Chaves-Arquero, Sunny Cai, Angelo Miguel Figueiredo, Stephen R Martin, Ian A. Taylor^*, Andres Ramos^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

10 Citations (Scopus)

Abstract

m6A methylation provides an essential layer of regulation in organismal development, and is aberrant in a range of cancers and neuro-pathologies. The information encoded by m6A methylation is integrated into existing RNA regulatory networks by RNA binding proteins that recognise methylated sites, the m6A readers. m6A readers include a well-characterised class of dedicated proteins, the YTH proteins, as well as a broader group of multi-functional regulators where recognition of m6A is only partially understood. Molecular insight in this recognition is essential to build a mechanistic understanding of global m6A regulation. In this study, we show that the reader IMP1 recognises the m6A using a dedicated hydrophobic platform that assembles on the methyl moiety, creating a stable high-affinity interaction. This recognition is conserved across evolution and independent from the underlying sequence context but is layered upon the strong sequence specificity of IMP1 for GGAC RNA. This leads us to propose a concept for m6A regulation where methylation plays a context-dependent role in the recognition of selected IMP1 targets that is dependent on the cellular concentration of available IMP1, differing from that observed for the YTH proteins.

Original language	English
Pages (from-to)	8774-8786
Number of pages	13
Journal	Nucleic Acids Research
Volume	51
Issue number	16
Early online date	8 Jun 2023
DOIs	https://doi.org/10.1093/nar/gkad534
Publication status	Published - 8 Sept 2023

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https://academic.oup.com/nar/article/51/16/8774/7209315

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title = "Direct m6A recognition by IMP1 underlays an alternative model of target selection for non-canonical methyl-readers",

abstract = "m6A methylation provides an essential layer of regulation in organismal development, and is aberrant in a range of cancers and neuro-pathologies. The information encoded by m6A methylation is integrated into existing RNA regulatory networks by RNA binding proteins that recognise methylated sites, the m6A readers. m6A readers include a well-characterised class of dedicated proteins, the YTH proteins, as well as a broader group of multi-functional regulators where recognition of m6A is only partially understood. Molecular insight in this recognition is essential to build a mechanistic understanding of global m6A regulation. In this study, we show that the reader IMP1 recognises the m6A using a dedicated hydrophobic platform that assembles on the methyl moiety, creating a stable high-affinity interaction. This recognition is conserved across evolution and independent from the underlying sequence context but is layered upon the strong sequence specificity of IMP1 for GGAC RNA. This leads us to propose a concept for m6A regulation where methylation plays a context-dependent role in the recognition of selected IMP1 targets that is dependent on the cellular concentration of available IMP1, differing from that observed for the YTH proteins.",

author = "Giancarlo Abis and Giuseppe Nicastro and Pierre Klein and Sofia Esteban-Serna and Christopher Gallagher and Belen Chaves-Arquero and Sunny Cai and Figueiredo, {Angelo Miguel} and Martin, {Stephen R} and Taylor, {Ian A.} and Andres Ramos",

note = "Funding Information: A.R. G.A. and P.K. are supported by the UK Medical Research Council [S000305/1]; A.R., together with B.C., is also supported by the UK BBRSC [S0114438/1]; I.A.T. and G.N. are supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK [CC2029]; UK Medical Research Council [CC2029]; Wellcome Trust [CC2029]; Francis Crick Institute also through provision of access to the MRC Biomedical NMR Centre (Francis Crick Institute core funding by Cancer Research UK [CC1078]; UK Medical Research Council [CC1078]; Wellcome Trust [CC1078]; R.P. is supported by an MRC Senior Clinical Fellowship [MR/S006591/1]; Lister Research Prize Fellowship. Funding for open access charge: UCL UKRI institutional grant. Funding Information: We thank the MRC UK biomedical NMR facility and the UCL NMR facility for access and assistance in data recording. This study made use of NMRbox: National Centre for Biomolecular NMR Data Processing and Analysis, a Biomedical Technology Research Resource (BTRR), which is supported by NIH grant P41GM111135 (NIGMS). We would also like to thank Jerne Ule for the stimulating discussion on the iCLIP data. Publisher Copyright: {\textcopyright} 2023 The Author(s).",

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doi = "10.1093/nar/gkad534",

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T1 - Direct m6A recognition by IMP1 underlays an alternative model of target selection for non-canonical methyl-readers

AU - Abis, Giancarlo

AU - Nicastro, Giuseppe

AU - Klein, Pierre

AU - Esteban-Serna, Sofia

AU - Gallagher, Christopher

AU - Chaves-Arquero, Belen

AU - Cai, Sunny

AU - Figueiredo, Angelo Miguel

AU - Martin, Stephen R

AU - Taylor, Ian A.

AU - Ramos, Andres

N1 - Funding Information: A.R. G.A. and P.K. are supported by the UK Medical Research Council [S000305/1]; A.R., together with B.C., is also supported by the UK BBRSC [S0114438/1]; I.A.T. and G.N. are supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK [CC2029]; UK Medical Research Council [CC2029]; Wellcome Trust [CC2029]; Francis Crick Institute also through provision of access to the MRC Biomedical NMR Centre (Francis Crick Institute core funding by Cancer Research UK [CC1078]; UK Medical Research Council [CC1078]; Wellcome Trust [CC1078]; R.P. is supported by an MRC Senior Clinical Fellowship [MR/S006591/1]; Lister Research Prize Fellowship. Funding for open access charge: UCL UKRI institutional grant. Funding Information: We thank the MRC UK biomedical NMR facility and the UCL NMR facility for access and assistance in data recording. This study made use of NMRbox: National Centre for Biomolecular NMR Data Processing and Analysis, a Biomedical Technology Research Resource (BTRR), which is supported by NIH grant P41GM111135 (NIGMS). We would also like to thank Jerne Ule for the stimulating discussion on the iCLIP data. Publisher Copyright: © 2023 The Author(s).

PY - 2023/9/8

Y1 - 2023/9/8

N2 - m6A methylation provides an essential layer of regulation in organismal development, and is aberrant in a range of cancers and neuro-pathologies. The information encoded by m6A methylation is integrated into existing RNA regulatory networks by RNA binding proteins that recognise methylated sites, the m6A readers. m6A readers include a well-characterised class of dedicated proteins, the YTH proteins, as well as a broader group of multi-functional regulators where recognition of m6A is only partially understood. Molecular insight in this recognition is essential to build a mechanistic understanding of global m6A regulation. In this study, we show that the reader IMP1 recognises the m6A using a dedicated hydrophobic platform that assembles on the methyl moiety, creating a stable high-affinity interaction. This recognition is conserved across evolution and independent from the underlying sequence context but is layered upon the strong sequence specificity of IMP1 for GGAC RNA. This leads us to propose a concept for m6A regulation where methylation plays a context-dependent role in the recognition of selected IMP1 targets that is dependent on the cellular concentration of available IMP1, differing from that observed for the YTH proteins.

AB - m6A methylation provides an essential layer of regulation in organismal development, and is aberrant in a range of cancers and neuro-pathologies. The information encoded by m6A methylation is integrated into existing RNA regulatory networks by RNA binding proteins that recognise methylated sites, the m6A readers. m6A readers include a well-characterised class of dedicated proteins, the YTH proteins, as well as a broader group of multi-functional regulators where recognition of m6A is only partially understood. Molecular insight in this recognition is essential to build a mechanistic understanding of global m6A regulation. In this study, we show that the reader IMP1 recognises the m6A using a dedicated hydrophobic platform that assembles on the methyl moiety, creating a stable high-affinity interaction. This recognition is conserved across evolution and independent from the underlying sequence context but is layered upon the strong sequence specificity of IMP1 for GGAC RNA. This leads us to propose a concept for m6A regulation where methylation plays a context-dependent role in the recognition of selected IMP1 targets that is dependent on the cellular concentration of available IMP1, differing from that observed for the YTH proteins.

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U2 - 10.1093/nar/gkad534

DO - 10.1093/nar/gkad534

M3 - Article

SN - 0305-1048

VL - 51

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EP - 8786

JO - Nucleic Acids Research

JF - Nucleic Acids Research

IS - 16

ER -

Direct m6A recognition by IMP1 underlays an alternative model of target selection for non-canonical methyl-readers

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