Abstract
The post-translational modification of DNA repair and checkpoint proteins by ubiquitin and small ubiquitin-like modifier (SUMO) critically orchestrates the DNA damage response (DDR). The ubiquitin ligase RNF4 integrates signaling by SUMO and ubiquitin, through its selective recognition and ubiquitination of SUMO-modified proteins. Here, we define a key new determinant for target discrimination by RNF4, in addition to interaction with SUMO. We identify a nucleosome-targeting motif within the RNF4 RING domain that can bind DNA and thereby enables RNF4 to selectively ubiquitinate nucleosomal histones. Furthermore, RNF4 nucleosome-targeting is crucially required for the repair of TRF2-depleted dysfunctional telomeres by 53BP1-mediated non-homologous end joining.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acid Motifs
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Animals
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Cell Line
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Chromosomal Proteins, Non-Histone / metabolism
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Crystallography, X-Ray
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DNA Damage
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DNA Repair*
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DNA-Binding Proteins / metabolism
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Gene Knockout Techniques
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Mice
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Nuclear Proteins / ultrastructure*
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Nucleosomes / metabolism*
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Protein Processing, Post-Translational
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Protein Structure, Tertiary
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Small Ubiquitin-Related Modifier Proteins / metabolism*
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Tamoxifen / analogs & derivatives
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Tamoxifen / pharmacology
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Telomere / drug effects
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Telomere / genetics
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Telomeric Repeat Binding Protein 2 / genetics
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription Factors / ultrastructure*
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Tumor Suppressor p53-Binding Protein 1
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Ubiquitin / metabolism
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Ubiquitin-Protein Ligases
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Ubiquitination
Substances
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Chromosomal Proteins, Non-Histone
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DNA-Binding Proteins
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Nuclear Proteins
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Nucleosomes
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Small Ubiquitin-Related Modifier Proteins
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TRF2 protein, mouse
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Telomeric Repeat Binding Protein 2
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Transcription Factors
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Trp53bp1 protein, mouse
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Tumor Suppressor p53-Binding Protein 1
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Ubiquitin
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Tamoxifen
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afimoxifene
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Rnf4 protein, mouse
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Ubiquitin-Protein Ligases