DNA binding analysis of rare variants in homeodomains reveals homeodomain specificity-determining residues

Kian Hong Kock, Patrick K. Kimes, Stephen S. Gisselbrecht, Sachi Inukai, Sabrina K. Phanor, James T. Anderson, Gayatri Ramakrishnan, Colin H. Lipper, Dongyuan Song, Jesse V. Kurland, Julia M. Rogers, Raehoon Jeong, Stephen C. Blacklow, Rafael A. Irizarry and Martha L. Bulyk ()
Additional contact information
Kian Hong Kock: Brigham and Women’s Hospital and Harvard Medical School
Patrick K. Kimes: Dana-Farber Cancer Institute
Stephen S. Gisselbrecht: Brigham and Women’s Hospital and Harvard Medical School
Sachi Inukai: Brigham and Women’s Hospital and Harvard Medical School
Sabrina K. Phanor: Brigham and Women’s Hospital and Harvard Medical School
James T. Anderson: Brigham and Women’s Hospital and Harvard Medical School
Gayatri Ramakrishnan: Brigham and Women’s Hospital and Harvard Medical School
Colin H. Lipper: Harvard Medical School
Dongyuan Song: Harvard T.H. Chan School of Public Health
Jesse V. Kurland: Brigham and Women’s Hospital and Harvard Medical School
Julia M. Rogers: Brigham and Women’s Hospital and Harvard Medical School
Raehoon Jeong: Brigham and Women’s Hospital and Harvard Medical School
Stephen C. Blacklow: Harvard University
Rafael A. Irizarry: Dana-Farber Cancer Institute
Martha L. Bulyk: Brigham and Women’s Hospital and Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Homeodomains (HDs) are the second largest class of DNA binding domains (DBDs) among eukaryotic sequence-specific transcription factors (TFs) and are the TF structural class with the largest number of disease-associated mutations in the Human Gene Mutation Database (HGMD). Despite numerous structural studies and large-scale analyses of HD DNA binding specificity, HD-DNA recognition is still not fully understood. Here, we analyze 92 human HD mutants, including disease-associated variants and variants of uncertain significance (VUS), for their effects on DNA binding activity. Many of the variants alter DNA binding affinity and/or specificity. Detailed biochemical analysis and structural modeling identifies 14 previously unknown specificity-determining positions, 5 of which do not contact DNA. The same missense substitution at analogous positions within different HDs often exhibits different effects on DNA binding activity. Variant effect prediction tools perform moderately well in distinguishing variants with altered DNA binding affinity, but poorly in identifying those with altered binding specificity. Our results highlight the need for biochemical assays of TF coding variants and prioritize dozens of variants for further investigations into their pathogenicity and the development of clinical diagnostics and precision therapies.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-47396-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47396-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-47396-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().