Mechanism of 53BP1 activity regulation by RNA-binding TIRR and a designer protein

Maria Victoria Botuyan, Gaofeng Cui, Pascal Drané, Catarina Oliveira, Alexandre Detappe, Marie Eve Brault, Nishita Parnandi, Shweta Chaubey, James R. Thompson, Benoît Bragantini, Debiao Zhao, J. Ross Chapman, Dipanjan Chowdhury, Georges Mer

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Dynamic protein interaction networks such as DNA double-strand break (DSB) signaling are modulated by post-translational modifications. The DNA repair factor 53BP1 is a rare example of a protein whose post-translational modification-binding function can be switched on and off. 53BP1 is recruited to DSBs by recognizing histone lysine methylation within chromatin, an activity directly inhibited by the 53BP1-binding protein TIRR. X-ray crystal structures of TIRR and a designer protein bound to 53BP1 now reveal a unique regulatory mechanism in which an intricate binding area centered on an essential TIRR arginine residue blocks the methylated-chromatin-binding surface of 53BP1. A 53BP1 separation-of-function mutation that abolishes TIRR-mediated regulation in cells renders 53BP1 hyperactive in response to DSBs, highlighting the key inhibitory function of TIRR. This 53BP1 inhibition is relieved by TIRR-interacting RNA molecules, providing proof-of-principle of RNA-triggered 53BP1 recruitment to DSBs.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalNature Structural and Molecular Biology
DOIs
StateAccepted/In press - Jul 2 2018

Fingerprint

RNA
Post Translational Protein Processing
Chromatin
Protein Interaction Maps
Proteins
Double-Stranded DNA Breaks
DNA Repair
Histones
Methylation
Lysine
Arginine
Carrier Proteins
X-Rays
Mutation
1,2-di-(4-sulfamidophenyl)-4-butylpyrazolidine-3,5-dione
Tumor Suppressor p53-Binding Protein 1

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Mechanism of 53BP1 activity regulation by RNA-binding TIRR and a designer protein. / Botuyan, Maria Victoria; Cui, Gaofeng; Drané, Pascal; Oliveira, Catarina; Detappe, Alexandre; Brault, Marie Eve; Parnandi, Nishita; Chaubey, Shweta; Thompson, James R.; Bragantini, Benoît; Zhao, Debiao; Chapman, J. Ross; Chowdhury, Dipanjan; Mer, Georges.

In: Nature Structural and Molecular Biology, 02.07.2018, p. 1-10.

Research output: Contribution to journalArticle

Botuyan, MV, Cui, G, Drané, P, Oliveira, C, Detappe, A, Brault, ME, Parnandi, N, Chaubey, S, Thompson, JR, Bragantini, B, Zhao, D, Chapman, JR, Chowdhury, D & Mer, G 2018, 'Mechanism of 53BP1 activity regulation by RNA-binding TIRR and a designer protein', Nature Structural and Molecular Biology, pp. 1-10. https://doi.org/10.1038/s41594-018-0083-z
Botuyan, Maria Victoria ; Cui, Gaofeng ; Drané, Pascal ; Oliveira, Catarina ; Detappe, Alexandre ; Brault, Marie Eve ; Parnandi, Nishita ; Chaubey, Shweta ; Thompson, James R. ; Bragantini, Benoît ; Zhao, Debiao ; Chapman, J. Ross ; Chowdhury, Dipanjan ; Mer, Georges. / Mechanism of 53BP1 activity regulation by RNA-binding TIRR and a designer protein. In: Nature Structural and Molecular Biology. 2018 ; pp. 1-10.
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