The molecular details of a novel phosphorylation-dependent interaction between MRN and the SOSS complex

Serene El-Kamand; Mark N. Adams; Jacqueline M. Matthews; Mar-Dean Du Plessis; Ben Crossett; Angela Connolly; Natasha Breen; Alexander Dudley; Derek J. Richard; Roland Gamsjaeger; Liza Cubeddu

doi:10.1002/pro.4782

The molecular details of a novel phosphorylation-dependent interaction between MRN and the SOSS complex

Serene El-Kamand, Mark N. Adams, Jacqueline M. Matthews, Mar-Dean Du Plessis, Ben Crossett, Angela Connolly, Natasha Breen, Alexander Dudley, Derek J. Richard, Roland Gamsjaeger, Liza Cubeddu

Western Sydney University

Research output: Contribution to journal › Article › peer-review

Abstract

The repair of double-strand DNA breaks (DSBs) by homologous recombination is crucial in the maintenance of genome integrity. While the key role of the Mre11-Rad50-Nbs1 (MRN) complex in repair is well known, hSSB1 (SOSSB and OBFC2B), one of the main components of the sensor of single-stranded DNA (SOSS) protein complex, has also been shown to rapidly localize to DSB breaks and promote repair. We have previously demonstrated that hSSB1 binds directly to Nbs1, a component of the MRN complex, in a DNA damage-independent manner. However, recruitment of the MRN complex has also been demonstrated by an interaction between Integrator Complex Subunit 3 (INTS3; also known as SOSSA), another member of the SOSS complex, and Nbs1. In this study, we utilize a combined approach of in silico, biochemical, and functional experiments to uncover the molecular details of INTS3 binding to Nbs1. We demonstrate that the forkhead-associated domain of Nbs1 interacts with INTS3 via phosphorylation-dependent binding to INTS3 at Threonine 592, with contributions from Serine 590. Based on these data, we propose a model of MRN recruitment to a DSB via INTS3.

Original language	English
Article number	e4782
Number of pages	12
Journal	Protein Science
Volume	32
Issue number	10
DOIs	https://doi.org/10.1002/pro.4782
Publication status	Published - Oct 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.

Open Access - Access Right Statement

© 2023 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Notes

WIP in RD

Keywords

DNA repair
hSSB1
INTS3
MRN complex
Nbs1
SOSS complex

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10.1002/pro.4782

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abstract = "The repair of double-strand DNA breaks (DSBs) by homologous recombination is crucial in the maintenance of genome integrity. While the key role of the Mre11-Rad50-Nbs1 (MRN) complex in repair is well known, hSSB1 (SOSSB and OBFC2B), one of the main components of the sensor of single-stranded DNA (SOSS) protein complex, has also been shown to rapidly localize to DSB breaks and promote repair. We have previously demonstrated that hSSB1 binds directly to Nbs1, a component of the MRN complex, in a DNA damage-independent manner. However, recruitment of the MRN complex has also been demonstrated by an interaction between Integrator Complex Subunit 3 (INTS3; also known as SOSSA), another member of the SOSS complex, and Nbs1. In this study, we utilize a combined approach of in silico, biochemical, and functional experiments to uncover the molecular details of INTS3 binding to Nbs1. We demonstrate that the forkhead-associated domain of Nbs1 interacts with INTS3 via phosphorylation-dependent binding to INTS3 at Threonine 592, with contributions from Serine 590. Based on these data, we propose a model of MRN recruitment to a DSB via INTS3.",

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author = "Serene El-Kamand and Adams, {Mark N.} and Matthews, {Jacqueline M.} and {Du Plessis}, Mar-Dean and Ben Crossett and Angela Connolly and Natasha Breen and Alexander Dudley and Richard, {Derek J.} and Roland Gamsjaeger and Liza Cubeddu",

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AU - Matthews, Jacqueline M.

AU - Du Plessis, Mar-Dean

AU - Crossett, Ben

AU - Connolly, Angela

AU - Breen, Natasha

AU - Dudley, Alexander

AU - Richard, Derek J.

AU - Gamsjaeger, Roland

AU - Cubeddu, Liza

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N2 - The repair of double-strand DNA breaks (DSBs) by homologous recombination is crucial in the maintenance of genome integrity. While the key role of the Mre11-Rad50-Nbs1 (MRN) complex in repair is well known, hSSB1 (SOSSB and OBFC2B), one of the main components of the sensor of single-stranded DNA (SOSS) protein complex, has also been shown to rapidly localize to DSB breaks and promote repair. We have previously demonstrated that hSSB1 binds directly to Nbs1, a component of the MRN complex, in a DNA damage-independent manner. However, recruitment of the MRN complex has also been demonstrated by an interaction between Integrator Complex Subunit 3 (INTS3; also known as SOSSA), another member of the SOSS complex, and Nbs1. In this study, we utilize a combined approach of in silico, biochemical, and functional experiments to uncover the molecular details of INTS3 binding to Nbs1. We demonstrate that the forkhead-associated domain of Nbs1 interacts with INTS3 via phosphorylation-dependent binding to INTS3 at Threonine 592, with contributions from Serine 590. Based on these data, we propose a model of MRN recruitment to a DSB via INTS3.

AB - The repair of double-strand DNA breaks (DSBs) by homologous recombination is crucial in the maintenance of genome integrity. While the key role of the Mre11-Rad50-Nbs1 (MRN) complex in repair is well known, hSSB1 (SOSSB and OBFC2B), one of the main components of the sensor of single-stranded DNA (SOSS) protein complex, has also been shown to rapidly localize to DSB breaks and promote repair. We have previously demonstrated that hSSB1 binds directly to Nbs1, a component of the MRN complex, in a DNA damage-independent manner. However, recruitment of the MRN complex has also been demonstrated by an interaction between Integrator Complex Subunit 3 (INTS3; also known as SOSSA), another member of the SOSS complex, and Nbs1. In this study, we utilize a combined approach of in silico, biochemical, and functional experiments to uncover the molecular details of INTS3 binding to Nbs1. We demonstrate that the forkhead-associated domain of Nbs1 interacts with INTS3 via phosphorylation-dependent binding to INTS3 at Threonine 592, with contributions from Serine 590. Based on these data, we propose a model of MRN recruitment to a DSB via INTS3.

KW - DNA repair

KW - hSSB1

KW - INTS3

KW - MRN complex

KW - Nbs1

KW - SOSS complex

UR - https://hdl.handle.net/1959.7/uws:72514

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JO - Protein Science

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The molecular details of a novel phosphorylation-dependent interaction between MRN and the SOSS complex

Abstract

Bibliographical note

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Keywords

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