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Impact of oligoarginine peptides in ribosome composition and chromatin proteomes

ABSTRACT: Expanded intronic GGGGCC repeats in C9ORF72 produce several dipeptides, from which the two that contain arginine, (PR)n and (GR)n, accumulate at nucleoli and kill cells. While this toxicity plays an important role in ALS pathogenesis, its mechanism remains unknown. We here show that PR dipeptides bind avidly to DNA and RNA, so that any cellular reaction involving nucleic acids is impaired by the dipeptides. Consistently, PR-induced cell death can be rescued by addition of non-coding oligonucleotides. Interestingly, the effects of PR dipeptides are to a large extent mimicked by protamine, a sperm-specific Arg-rich protein, and the toxicity of either protamine or PR dipeptides is rescued by the anticoagulant heparin. We propose that the generalized coating of nucleic acids by Arg-rich peptides accounts for the toxicity of C9ORF72 mutations in ALS.

INSTRUMENT(S): maXis, Q Exactive

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

DISEASE(S): Amyotrophic Lateral Sclerosis

SUBMITTER: Eduardo Zarzuela

LAB HEAD: Oscar Fernández Capetillo

PROVIDER: PXD010555 | Pride | 2021-04-12

REPOSITORIES: Pride

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			Action	DRS
	20170928_EZ_Vanesa_10_2-C2_01_11467.d.zip	Other
	20170928_EZ_Vanesa_10_2-C2_01_11482.d.zip	Other
	20170928_EZ_Vanesa_11_2-C3_01_11468.d.zip	Other
	20170928_EZ_Vanesa_11_2-C3_01_11483.d.zip	Other
	20170928_EZ_Vanesa_12_2-C4_01_11469.d.zip	Other

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Impact of oligoarginine peptides in RNA-binding proteomes

Project description:Expanded intronic GGGGCC repeats in C9ORF72 produce several dipeptides, from which the two that contain arginine, (PR)n and (GR)n, accumulate at nucleoli and kill cells. While this toxicity plays an important role in ALS pathogenesis, its mechanism remains unknown. We here show that PR dipeptides bind avidly to DNA and RNA, so that any cellular reaction involving nucleic acids is impaired by the dipeptides. Consistently, PR-induced cell death can be rescued by addition of non-coding oligonucleotides. Interestingly, the effects of PR dipeptides are to a large extent mimicked by protamine, a sperm-specific Arg-rich protein, and the toxicity of either protamine or PR dipeptides is rescued by the anticoagulant heparin. We propose that the generalized coating of nucleic acids by Arg-rich peptides accounts for the toxicity of C9ORF72 mutations in ALS.

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