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

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 struc...

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Bibliographic Details
Published in:Cellular and molecular life sciences : CMLS 2021-12, Vol.78 (23), p.7519-7536
Main Authors: 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, Rasko, John E. J.
Format: Article
Language:English
Subjects:
Apoptosis
Binding
Biochemistry
Biomedical and Life Sciences
Biomedicine
Cancer
CCCTC-Binding Factor - chemistry
CCCTC-Binding Factor - genetics
CCCTC-Binding Factor - metabolism
Cell Biology
Cell Proliferation
Cellular structure
Chromatin
Deoxyribonucleic acid
DNA
Gene Expression Regulation, Neoplastic
Gene regulation
Humans
Life Sciences
Molecular docking
Molecular dynamics
Mutation
Neoplasms - genetics
Neoplasms - metabolism
Neoplasms - pathology
Original
Original Article
Phenotype
Phenotypes
Promoter Regions, Genetic
Residues
Structure-Activity Relationship
Structure-function relationships
Transcription
Tumor Cells, Cultured
Tumor suppressor genes
Tumors
Zinc
Zinc finger proteins
Zinc Fingers
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Summary: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.
ISSN:1420-682X
1420-9071
DOI:10.1007/s00018-021-03946-z