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

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

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1007/s00018-021-03946-z
Journal or Publication Title: Cellular and Molecular Life Sciences
Volume: 78
Number: 23
Page Range: pp. 7519-7536
Date: December 2021
Divisions: Gene and Stem Cell Therapy
Depositing User: General Admin
Identification Number: 10.1007/s00018-021-03946-z
ISSN: 1420-682X
Date Deposited: 08 Dec 2021 00:10
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.

Keywords: CTCF; Cancer; Gain-of-function; Loss-of-function; Molecular docking; Molecular dynamics; Somatic mutation; Zinc finger.

© 2021. The Author(s).

Creators:
Creators
Email
Bailey, Charles G.
UNSPECIFIED
Gupta, Shailendra
UNSPECIFIED
Metierre, Cynthia
UNSPECIFIED
Amarasekera, Punkaja M. S.
UNSPECIFIED
O’Young, Patrick
UNSPECIFIED
Kyaw, Wunna
UNSPECIFIED
Laletin, Tatyana
UNSPECIFIED
Francis, Habib
UNSPECIFIED
Semaan, Crystal
UNSPECIFIED
Sharifi Tabar, Mehdi
UNSPECIFIED
Singh, Krishna P.
UNSPECIFIED
Mullighan, Charles G.
UNSPECIFIED
Wolkenhauer, Olaf
UNSPECIFIED
Schmitz, Ulf
UNSPECIFIED
Rasko, John E. J.
UNSPECIFIED
Last Modified: 08 Dec 2021 00:10
URI: https://eprints.centenary.org.au/id/eprint/1149

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