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...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-11-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-01832-z |
| _version_ | 1818857851193393152 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-19T08:46:57Z |
| format | Article |
| id | doaj.art-29cec673a8804bdeae490fdb3c8d0364 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-19T08:46:57Z |
| publishDate | 2021-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-29cec673a8804bdeae490fdb3c8d03642022-12-21T20:28:47ZengNature PortfolioScientific Reports2045-23222021-11-0111111510.1038/s41598-021-01832-zMutational signatures in GATA3 transcription factor and its DNA binding domain that stimulate breast cancer and HDR syndromeAtlal El-Assaad0Zaher Dawy1Athar Khalil2Georges Nemer3Department of Electrical and Computer Engineering, American University of Beirut (AUB)Department of Electrical and Computer Engineering, American University of Beirut (AUB)Department of Biochemistry and Molecular Genetics, American University of Beirut (AUB)Department of Biochemistry and Molecular Genetics, American University of Beirut (AUB)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.https://doi.org/10.1038/s41598-021-01832-z |
| spellingShingle | 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 Scientific Reports |
| title | 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_short | 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 |
| url | https://doi.org/10.1038/s41598-021-01832-z |
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