Mutational signatures in GATA3 transcription factor and its DNA binding domain that stimulate breast cancer and HDR syndrome

Abstract Transcription factors (TFs) play important roles in many biochemical processes. Many human genetic disorders have been associated with mutations in the genes encoding these transcription factors, and so those mutations became targets for medications and drug design. In parallel, since many...

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Autores principales:	Atlal El-Assaad, Zaher Dawy, Athar Khalil, Georges Nemer
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/29cec673a8804bdeae490fdb3c8d0364
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spelling	oai:doaj.org-article:29cec673a8804bdeae490fdb3c8d03642021-11-28T12:16:11ZMutational signatures in GATA3 transcription factor and its DNA binding domain that stimulate breast cancer and HDR syndrome10.1038/s41598-021-01832-z2045-2322https://doaj.org/article/29cec673a8804bdeae490fdb3c8d03642021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-01832-zhttps://doaj.org/toc/2045-2322Abstract Transcription factors (TFs) play important roles in many biochemical processes. Many human genetic disorders have been associated with mutations in the genes encoding these transcription factors, and so those mutations became targets for medications and drug design. In parallel, since many transcription factors act either as tumor suppressors or oncogenes, their mutations are mostly associated with cancer. In this perspective, we studied the GATA3 transcription factor when bound to DNA in a crystal structure and assessed the effect of different mutations encountered in patients with different diseases and phenotypes. We generated all missense mutants of GATA3 protein and DNA within the adjacent and the opposite GATA3:DNA complex models. We mutated every amino acid and studied the new binding of the complex after each mutation. Similarly, we did for every DNA base. We applied Poisson-Boltzmann electrostatic calculations feeding into free energy calculations. After analyzing our data, we identified amino acids and DNA bases keys for binding. Furthermore, we validated those findings against experimental genetic data. Our results are the first to propose in silico modeling for GATA:DNA bound complexes that could be used to score effects of missense mutations in other classes of transcription factors involved in common and genetic diseases.Atlal El-AssaadZaher DawyAthar KhalilGeorges NemerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Atlal El-Assaad Zaher Dawy Athar Khalil Georges Nemer Mutational signatures in GATA3 transcription factor and its DNA binding domain that stimulate breast cancer and HDR syndrome
description	Abstract Transcription factors (TFs) play important roles in many biochemical processes. Many human genetic disorders have been associated with mutations in the genes encoding these transcription factors, and so those mutations became targets for medications and drug design. In parallel, since many transcription factors act either as tumor suppressors or oncogenes, their mutations are mostly associated with cancer. In this perspective, we studied the GATA3 transcription factor when bound to DNA in a crystal structure and assessed the effect of different mutations encountered in patients with different diseases and phenotypes. We generated all missense mutants of GATA3 protein and DNA within the adjacent and the opposite GATA3:DNA complex models. We mutated every amino acid and studied the new binding of the complex after each mutation. Similarly, we did for every DNA base. We applied Poisson-Boltzmann electrostatic calculations feeding into free energy calculations. After analyzing our data, we identified amino acids and DNA bases keys for binding. Furthermore, we validated those findings against experimental genetic data. Our results are the first to propose in silico modeling for GATA:DNA bound complexes that could be used to score effects of missense mutations in other classes of transcription factors involved in common and genetic diseases.
format	article
author	Atlal El-Assaad Zaher Dawy Athar Khalil Georges Nemer
author_facet	Atlal El-Assaad Zaher Dawy Athar Khalil Georges Nemer
author_sort	Atlal El-Assaad
title	Mutational signatures in GATA3 transcription factor and its DNA binding domain that stimulate breast cancer and HDR syndrome
title_short	Mutational signatures in GATA3 transcription factor and its DNA binding domain that stimulate breast cancer and HDR syndrome
title_full	Mutational signatures in GATA3 transcription factor and its DNA binding domain that stimulate breast cancer and HDR syndrome
title_fullStr	Mutational signatures in GATA3 transcription factor and its DNA binding domain that stimulate breast cancer and HDR syndrome
title_full_unstemmed	Mutational signatures in GATA3 transcription factor and its DNA binding domain that stimulate breast cancer and HDR syndrome
title_sort	mutational signatures in gata3 transcription factor and its dna binding domain that stimulate breast cancer and hdr syndrome
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/29cec673a8804bdeae490fdb3c8d0364
work_keys_str_mv	AT atlalelassaad mutationalsignaturesingata3transcriptionfactoranditsdnabindingdomainthatstimulatebreastcancerandhdrsyndrome AT zaherdawy mutationalsignaturesingata3transcriptionfactoranditsdnabindingdomainthatstimulatebreastcancerandhdrsyndrome AT atharkhalil mutationalsignaturesingata3transcriptionfactoranditsdnabindingdomainthatstimulatebreastcancerandhdrsyndrome AT georgesnemer mutationalsignaturesingata3transcriptionfactoranditsdnabindingdomainthatstimulatebreastcancerandhdrsyndrome
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Mutational signatures in GATA3 transcription factor and its DNA binding domain that stimulate breast cancer and HDR syndrome

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