Transcriptome-wide RNA binding analysis of C9orf72 poly(PR) dipeptides

被引：6

作者：

Balendra, Rubika ^{[1
,2
]}

de los Mozos, Igor Ruiz ^{[3
,4
,5
]}

Odeh, Hana M. ^{[6
]}

Glaria, Idoia ^{[1
,2
,7
]}

Milioto, Carmelo ^{[1
,2
]}

Wilson, Katherine M. ^{[1
,2
]}

Ule, Agnieszka M. ^{[5
]}

Hallegger, Martina ^{[3
]}

Masino, Laura ^{[8
]}

Martin, Stephen ^{[8
]}

Patani, Rickie ^{[3
]}

Shorter, James ^{[6
]}

Ule, Jernej ^{[3
,5
,9
]}

Isaacs, Adrian M. ^{[1
,2
]}

机构：

[1] UK Dementia Res Inst UCL, London, England

[2] UCL Queen Sq Inst Neurol, Dept Neurodegenerat Dis, London, England

[3] Francis Crick Inst, London, England

[4] Govt Navarra, Dept Personalized Med, NASERTIC, Pamplona, Spain

[5] UCL Queen Sq Inst Neurol, Dept Neuromuscular Dis, London, England

[6] Univ Penn, Dept Biochem & Biophys, Perelman Sch Med, Philadelphia, PA USA

[7] Govt Navarra, Inst Agrobiotechnol, Res Support Serv, CSIC, Mutilva, Spain

[8] Francis Crick Inst, Struct Biol Sci Technol Platform, London, England

[9] Kings Coll London, Maurice Wohl Clin Neurosci Inst, UK Dementia Res Inst, London, England

来源：

LIFE SCIENCE ALLIANCE | 2023年 / 6卷 / 09期

基金：

欧洲研究理事会; 英国惠康基金; 英国医学研究理事会;

关键词：

REPEAT EXPANSION; HEXANUCLEOTIDE REPEAT; PHASE-TRANSITION; GGGGCC REPEAT; PROTEINS; STRESS; ALS; SEPARATION;

D O I：

10.26508/lsa.202201824

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

An intronic GGGGCC repeat expansion in C9orf72 is a common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. The repeats are transcribed in both sense and antisense directions to generate distinct dipeptide repeat proteins, of which poly(GA), poly(GR), and poly(PR) have been implicated in contributing to neurodegeneration. Poly(PR) binding to RNA may contribute to toxicity, but analysis of poly(PR)-RNA binding on a transcriptomewide scale has not yet been carried out. We therefore performed crosslinking and immunoprecipitation (CLIP) analysis in human cells to identify the RNA binding sites of poly(PR). We found that poly(PR) binds to nearly 600 RNAs, with the sequence GAAGA enriched at the binding sites. In vitro experiments showed that poly(GAAGA) RNA binds poly(PR) with higher affinity than control RNA and induces the phase separation of poly(PR) into condensates. These data indicate that poly(PR) preferentially binds to poly(GAAGA)-containing RNAs, which may have physiological consequences.

引用

页数：11

共 44 条

[1] Unconventional Translation of C9ORF72 GGGGCC Expansion Generates Insoluble Polypeptides Specific to c9FTD/ALS [J].

Ash, Peter E. A. ;

Bieniek, Kevin F. ;

Gendron, Tania F. ;

Caulfield, Thomas ;

Lin, Wen-Lang ;

DeJesus-Hernandez, Mariely ;

van Blitterswijk, Marka M. ;

Jansen-West, Karen ;

Paul, Joseph W., III ;

Rademakers, Rosa ;

Boylan, Kevin B. ;

Dickson, Dennis W. ;

Petrucelli, Leonard .

NEURON, 2013, 77 (04) :639-646

[2] DREME: motif discovery in transcription factor ChIP-seq data [J].

Bailey, Timothy L. .

BIOINFORMATICS, 2011, 27 (12) :1653-1659

[3] C9orf72-mediated ALS and FTD: multiple pathways to disease [J].

Balendra, Rubika ;

Isaacs, Adrian M. .

NATURE REVIEWS NEUROLOGY, 2018, 14 (09) :544-558

[4] Spontaneous driving forces give rise to protein-RNA condensates with coexisting phases and complex material properties [J].

Boeynaems, Steven ;

Holehouse, Alex S. ;

Weinhardt, Venera ;

Kovacs, Denes ;

Van Lindt, Joris ;

Larabell, Carolyn ;

Van Den Bosch, Ludo ;

Das, Rhiju ;

Tompa, Peter S. ;

Pappu, Rohit, V ;

Gitler, Aaron D. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2019, 116 (16) :7889-7898

[5] Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics [J].

Boeynaems, Steven ;

Bogaert, Elke ;

Kovacs, Denes ;

Konijnenberg, Albert ;

Timmerman, Evy ;

Volkov, Alex ;

Guharoy, Mainak ;

De Decker, Mathias ;

Jaspers, Tom ;

Ryan, Veronica H. ;

Janke, Abigail M. ;

Baatsen, Pieter ;

Vercruysse, Thomas ;

Kolaitis, Regina-Maria ;

Daelemans, Dirk ;

Taylor, J. Paul ;

Kedersha, Nancy ;

Anderson, Paul ;

Impens, Francis ;

Sobott, Frank ;

Schymkowitz, Joost ;

Rousseau, Frederic ;

Fawzi, Nicolas L. ;

Robberecht, Wim ;

Van Damme, Philip ;

Tompa, Peter ;

Van Den Bosch, Ludo .

MOLECULAR CELL, 2017, 65 (06) :1044-+

[6] Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD [J].

Boeynaems, Steven ;

Bogaertl, Elke ;

Michiels, Emiel ;

Gijselinck, Ilse ;

Sieben, Anne ;

Jovicic, Ana ;

De Baets, Greet ;

Scheveneels, Wendy ;

Steyaert, Jolien ;

Cuijt, Ivy ;

Verstrepen, Kevin J. ;

Callaerts, Patrick ;

Rousseau, Frederic ;

Schymkowitz, Joost ;

Cruts, Marc ;

Van Broeckhoven, Christine ;

Van Damme, Philip ;

Gitler, Aaron D. ;

Robberecht, Wim ;

Van den Bosch, Ludo .

SCIENTIFIC REPORTS, 2016, 6

[7] Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS [J].

DeJesus-Hernandez, Mariely ;

Mackenzie, Ian R. ;

Boeve, Bradley F. ;

Boxer, Adam L. ;

Baker, Matt ;

Rutherford, Nicola J. ;

Nicholson, Alexandra M. ;

Finch, NiCole A. ;

Flynn, Heather ;

Adamson, Jennifer ;

Kouri, Naomi ;

Wojtas, Aleksandra ;

Sengdy, Pheth ;

Hsiung, Ging-Yuek R. ;

Karydas, Anna ;

Seeley, William W. ;

Josephs, Keith A. ;

Coppola, Giovanni ;

Geschwind, Daniel H. ;

Wszolek, Zbigniew K. ;

Feldman, Howard ;

Knopman, David S. ;

Petersen, Ronald C. ;

Miller, Bruce L. ;

Dickson, Dennis W. ;

Boylan, Kevin B. ;

Graff-Radford, Neill R. ;

Rademakers, Rosa .

NEURON, 2011, 72 (02) :245-256

[8] Sequence, Structure, and Context Preferences of Human RNA Binding Proteins [J].

Dominguez, Daniel ;

Freese, Peter ;

Alexis, Maria S. ;

Su, Amanda ;

Hochman, Myles ;

Palden, Tsultrim ;

Bazile, Cassandra ;

Lambert, Nicole J. ;

Van Nostrand, Eric L. ;

Pratt, Gabriel A. ;

Yeo, Gene W. ;

Graveley, Brenton R. ;

Burge, Christopher B. .

MOLECULAR CELL, 2018, 70 (05) :854-+

[9] GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport [J].

Freibaum, Brian D. ;

Lu, Yubing ;

Lopez-Gonzalez, Rodrigo ;

Kim, Nam Chul ;

Almeida, Sandra ;

Lee, Kyung-Ha ;

Badders, Nisha ;

Valentine, Marc ;

Miller, Bruce L. ;

Wong, Philip C. ;

Petrucelli, Leonard ;

Kim, Hong Joo ;

Gao, Fen-Biao ;

Taylor, J. Paul .

NATURE, 2015, 525 (7567) :129-+

[10] C9orf72 nucleotide repeat structures initiate molecular cascades of disease [J].

Haeusler, Aaron R. ;

Donnelly, Christopher J. ;

Periz, Goran ;

Simko, Eric A. J. ;

Shaw, Patrick G. ;

Kim, Min-Sik ;

Maragakis, Nicholas J. ;

Troncoso, Juan C. ;

Pandey, Akhilesh ;

Sattler, Rita ;

Rothstein, Jeffrey D. ;

Wang, Jiou .

NATURE, 2014, 507 (7491) :195-+

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