Structure–function relationships explain CTCF zinc finger mutation phenotypes in cancer

Bailey, Charles G., Gupta, Shailendra, Metierre, Cynthia, Amarasekera, Punkaja M.S., O'Young, Patrick, Kyaw, Wunna, Laletin, Tatyana, Francis, Habib, Semaan, Crystal, Sharifi Tabar, Mehdi, Singh, Krishna P., Mullighan, Charles G., Wolkenhauer, Olaf, Schmitz, Ulf, and Rasko, John (2021) Structure–function relationships explain CTCF zinc finger mutation phenotypes in cancer. Cellular and Molecular Life Sciences. (In Press)

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Abstract

CCCTC-binding factor (CTCF) plays fundamental roles in transcriptional regulation and chromatin architecture maintenance. CTCF is also a tumour suppressor frequently mutated in cancer, however, the structural and functional impact of mutations have not been examined. We performed molecular and structural characterisation of five cancer-specific CTCF missense zinc finger (ZF) mutations occurring within key intra- and inter-ZF residues. Functional characterisation of CTCF ZF mutations revealed a complete (L309P, R339W, R377H) or intermediate (R339Q) abrogation as well as an enhancement (G420D) of the anti-proliferative effects of CTCF. DNA binding at select sites was disrupted and transcriptional regulatory activities abrogated. Molecular docking and molecular dynamics confirmed that mutations in residues specifically contacting DNA bases or backbone exhibited loss of DNA binding. However, R339Q and G420D were stabilised by the formation of new primary DNA bonds, contributing to gain-of-function. Our data confirm that a spectrum of loss-, change- and gain-of-function impacts on CTCF zinc fingers are observed in cell growth regulation and gene regulatory activities. Hence, diverse cellular phenotypes of mutant CTCF are clearly explained by examining structure–function relationships.

Item ID: 69687
Item Type: Article (Research - C1)
ISSN: 1420-9071
Keywords: CTCF, Cancer, Zinc finger, Somatic mutation, Gain-of-function, Loss-of-function, Molecular docking, Molecular dynamics
Copyright Information: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adapta-tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Date Deposited: 21 Oct 2021 02:54
FoR Codes: 31 BIOLOGICAL SCIENCES > 3101 Biochemistry and cell biology > 310112 Structural biology (incl. macromolecular modelling) @ 33%
31 BIOLOGICAL SCIENCES > 3101 Biochemistry and cell biology > 310109 Proteomics and intermolecular interactions (excl. medical proteomics) @ 33%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3211 Oncology and carcinogenesis > 321101 Cancer cell biology @ 34%
SEO Codes: 28 EXPANDING KNOWLEDGE > 2801 Expanding knowledge > 280102 Expanding knowledge in the biological sciences @ 90%
28 EXPANDING KNOWLEDGE > 2801 Expanding knowledge > 280103 Expanding knowledge in the biomedical and clinical sciences @ 10%
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