Biochemical and structural characterization of analogs of MRE11 breast cancer-associated mutant F237C

Abstract The MRE11–RAD50–NBS1 (MRN) protein complex plays a vital role in DNA double strand break sensing, signaling, and repair. Mutation in any component of this complex may lead to disease as disrupting DNA double strand break repair has the potential to cause translocations and loss of genomic i...

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Autores principales:	Samiur Rahman, Mahtab Beikzadeh, Michael P. Latham
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9c5f84c227e2485fb31d59920f849eb5
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spelling	oai:doaj.org-article:9c5f84c227e2485fb31d59920f849eb52021-12-02T14:23:23ZBiochemical and structural characterization of analogs of MRE11 breast cancer-associated mutant F237C10.1038/s41598-021-86552-02045-2322https://doaj.org/article/9c5f84c227e2485fb31d59920f849eb52021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-86552-0https://doaj.org/toc/2045-2322Abstract The MRE11–RAD50–NBS1 (MRN) protein complex plays a vital role in DNA double strand break sensing, signaling, and repair. Mutation in any component of this complex may lead to disease as disrupting DNA double strand break repair has the potential to cause translocations and loss of genomic information. Here, we have investigated an MRE11 mutation, F237C, identified in a breast cancer tumor. We found that the analogous mutant of Pyrococcus furiosus Mre11 diminishes both the exonuclease and endonuclease activities of Mre11 in vitro. Solution state NMR experiments show that this mutant causes structural changes in the DNA-bound Mre11 for both exo- and endonuclease substrates and causes the protein to become generally more rigid. Moreover, by comparing the NMR data for this cancer-associated mutant with two previously described Mre11 separation-of-nuclease function mutants, a potential allosteric network was detected within Mre11 that connects the active site to regions responsible for recognizing the DNA ends and for dimerization. Together, our data further highlight the dynamics required for Mre11 nuclease function and illuminate the presence of allostery within the enzyme.Samiur RahmanMahtab BeikzadehMichael P. LathamNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Samiur Rahman Mahtab Beikzadeh Michael P. Latham Biochemical and structural characterization of analogs of MRE11 breast cancer-associated mutant F237C
description	Abstract The MRE11–RAD50–NBS1 (MRN) protein complex plays a vital role in DNA double strand break sensing, signaling, and repair. Mutation in any component of this complex may lead to disease as disrupting DNA double strand break repair has the potential to cause translocations and loss of genomic information. Here, we have investigated an MRE11 mutation, F237C, identified in a breast cancer tumor. We found that the analogous mutant of Pyrococcus furiosus Mre11 diminishes both the exonuclease and endonuclease activities of Mre11 in vitro. Solution state NMR experiments show that this mutant causes structural changes in the DNA-bound Mre11 for both exo- and endonuclease substrates and causes the protein to become generally more rigid. Moreover, by comparing the NMR data for this cancer-associated mutant with two previously described Mre11 separation-of-nuclease function mutants, a potential allosteric network was detected within Mre11 that connects the active site to regions responsible for recognizing the DNA ends and for dimerization. Together, our data further highlight the dynamics required for Mre11 nuclease function and illuminate the presence of allostery within the enzyme.
format	article
author	Samiur Rahman Mahtab Beikzadeh Michael P. Latham
author_facet	Samiur Rahman Mahtab Beikzadeh Michael P. Latham
author_sort	Samiur Rahman
title	Biochemical and structural characterization of analogs of MRE11 breast cancer-associated mutant F237C
title_short	Biochemical and structural characterization of analogs of MRE11 breast cancer-associated mutant F237C
title_full	Biochemical and structural characterization of analogs of MRE11 breast cancer-associated mutant F237C
title_fullStr	Biochemical and structural characterization of analogs of MRE11 breast cancer-associated mutant F237C
title_full_unstemmed	Biochemical and structural characterization of analogs of MRE11 breast cancer-associated mutant F237C
title_sort	biochemical and structural characterization of analogs of mre11 breast cancer-associated mutant f237c
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/9c5f84c227e2485fb31d59920f849eb5
work_keys_str_mv	AT samiurrahman biochemicalandstructuralcharacterizationofanalogsofmre11breastcancerassociatedmutantf237c AT mahtabbeikzadeh biochemicalandstructuralcharacterizationofanalogsofmre11breastcancerassociatedmutantf237c AT michaelplatham biochemicalandstructuralcharacterizationofanalogsofmre11breastcancerassociatedmutantf237c
_version_	1718391441252679680

Biochemical and structural characterization of analogs of MRE11 breast cancer-associated mutant F237C

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