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Targeting Phosphopeptide Recognition by the Human BRCA1 Tandem BRCT Domain to Interrupt BRCA1-Dependent Signaling

Intracellular signals triggered by DNA breakage flow through proteins containing BRCT (BRCA1 C-terminal) domains. This family, comprising 23 conserved phosphopeptide-binding modules in man, is inaccessible to small-molecule chemical inhibitors. Here, we develop Bractoppin, a drug-like inhibitor of p...

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Autores principales: Periasamy, Jayaprakash, Kurdekar, Vadiraj, Jasti, Subbarao, Nijaguna, Mamatha B., Boggaram, Sanjana, Hurakadli, Manjunath A., Raina, Dhruv, Kurup, Lokavya Meenakshi, Chintha, Chetan, Manjunath, Kavyashree, Goyal, Aneesh, Sadasivam, Gayathri, Bharatham, Kavitha, Padigaru, Muralidhara, Potluri, Vijay, Venkitaraman, Ashok R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015222/
https://www.ncbi.nlm.nih.gov/pubmed/29606576
http://dx.doi.org/10.1016/j.chembiol.2018.02.012
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author Periasamy, Jayaprakash
Kurdekar, Vadiraj
Jasti, Subbarao
Nijaguna, Mamatha B.
Boggaram, Sanjana
Hurakadli, Manjunath A.
Raina, Dhruv
Kurup, Lokavya Meenakshi
Chintha, Chetan
Manjunath, Kavyashree
Goyal, Aneesh
Sadasivam, Gayathri
Bharatham, Kavitha
Padigaru, Muralidhara
Potluri, Vijay
Venkitaraman, Ashok R.
author_facet Periasamy, Jayaprakash
Kurdekar, Vadiraj
Jasti, Subbarao
Nijaguna, Mamatha B.
Boggaram, Sanjana
Hurakadli, Manjunath A.
Raina, Dhruv
Kurup, Lokavya Meenakshi
Chintha, Chetan
Manjunath, Kavyashree
Goyal, Aneesh
Sadasivam, Gayathri
Bharatham, Kavitha
Padigaru, Muralidhara
Potluri, Vijay
Venkitaraman, Ashok R.
author_sort Periasamy, Jayaprakash
collection PubMed
description Intracellular signals triggered by DNA breakage flow through proteins containing BRCT (BRCA1 C-terminal) domains. This family, comprising 23 conserved phosphopeptide-binding modules in man, is inaccessible to small-molecule chemical inhibitors. Here, we develop Bractoppin, a drug-like inhibitor of phosphopeptide recognition by the human BRCA1 tandem (t)BRCT domain, which selectively inhibits substrate binding with nanomolar potency in vitro. Structure-activity exploration suggests that Bractoppin engages BRCA1 tBRCT residues recognizing pSer in the consensus motif, pSer-Pro-Thr-Phe, plus an abutting hydrophobic pocket that is distinct in structurally related BRCT domains, conferring selectivity. In cells, Bractoppin inhibits substrate recognition detected by Förster resonance energy transfer, and diminishes BRCA1 recruitment to DNA breaks, in turn suppressing damage-induced G2 arrest and assembly of the recombinase, RAD51. But damage-induced MDC1 recruitment, single-stranded DNA (ssDNA) generation, and TOPBP1 recruitment remain unaffected. Thus, an inhibitor of phosphopeptide recognition selectively interrupts BRCA1 tBRCT-dependent signals evoked by DNA damage.
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spelling pubmed-60152222018-06-26 Targeting Phosphopeptide Recognition by the Human BRCA1 Tandem BRCT Domain to Interrupt BRCA1-Dependent Signaling Periasamy, Jayaprakash Kurdekar, Vadiraj Jasti, Subbarao Nijaguna, Mamatha B. Boggaram, Sanjana Hurakadli, Manjunath A. Raina, Dhruv Kurup, Lokavya Meenakshi Chintha, Chetan Manjunath, Kavyashree Goyal, Aneesh Sadasivam, Gayathri Bharatham, Kavitha Padigaru, Muralidhara Potluri, Vijay Venkitaraman, Ashok R. Cell Chem Biol Article Intracellular signals triggered by DNA breakage flow through proteins containing BRCT (BRCA1 C-terminal) domains. This family, comprising 23 conserved phosphopeptide-binding modules in man, is inaccessible to small-molecule chemical inhibitors. Here, we develop Bractoppin, a drug-like inhibitor of phosphopeptide recognition by the human BRCA1 tandem (t)BRCT domain, which selectively inhibits substrate binding with nanomolar potency in vitro. Structure-activity exploration suggests that Bractoppin engages BRCA1 tBRCT residues recognizing pSer in the consensus motif, pSer-Pro-Thr-Phe, plus an abutting hydrophobic pocket that is distinct in structurally related BRCT domains, conferring selectivity. In cells, Bractoppin inhibits substrate recognition detected by Förster resonance energy transfer, and diminishes BRCA1 recruitment to DNA breaks, in turn suppressing damage-induced G2 arrest and assembly of the recombinase, RAD51. But damage-induced MDC1 recruitment, single-stranded DNA (ssDNA) generation, and TOPBP1 recruitment remain unaffected. Thus, an inhibitor of phosphopeptide recognition selectively interrupts BRCA1 tBRCT-dependent signals evoked by DNA damage. Cell Press 2018-06-21 /pmc/articles/PMC6015222/ /pubmed/29606576 http://dx.doi.org/10.1016/j.chembiol.2018.02.012 Text en © 2018 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Periasamy, Jayaprakash
Kurdekar, Vadiraj
Jasti, Subbarao
Nijaguna, Mamatha B.
Boggaram, Sanjana
Hurakadli, Manjunath A.
Raina, Dhruv
Kurup, Lokavya Meenakshi
Chintha, Chetan
Manjunath, Kavyashree
Goyal, Aneesh
Sadasivam, Gayathri
Bharatham, Kavitha
Padigaru, Muralidhara
Potluri, Vijay
Venkitaraman, Ashok R.
Targeting Phosphopeptide Recognition by the Human BRCA1 Tandem BRCT Domain to Interrupt BRCA1-Dependent Signaling
title Targeting Phosphopeptide Recognition by the Human BRCA1 Tandem BRCT Domain to Interrupt BRCA1-Dependent Signaling
title_full Targeting Phosphopeptide Recognition by the Human BRCA1 Tandem BRCT Domain to Interrupt BRCA1-Dependent Signaling
title_fullStr Targeting Phosphopeptide Recognition by the Human BRCA1 Tandem BRCT Domain to Interrupt BRCA1-Dependent Signaling
title_full_unstemmed Targeting Phosphopeptide Recognition by the Human BRCA1 Tandem BRCT Domain to Interrupt BRCA1-Dependent Signaling
title_short Targeting Phosphopeptide Recognition by the Human BRCA1 Tandem BRCT Domain to Interrupt BRCA1-Dependent Signaling
title_sort targeting phosphopeptide recognition by the human brca1 tandem brct domain to interrupt brca1-dependent signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015222/
https://www.ncbi.nlm.nih.gov/pubmed/29606576
http://dx.doi.org/10.1016/j.chembiol.2018.02.012
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