Tumor-associated zinc finger mutations in the CTCF transcription factor selectively alter its DNA-binding specificity

Galina N. Filippova; Jonathan E. Ulmer; James M. Moore; Michael D. Ward; Ying J. Hu; Paul E. Neiman; Steven J. Collins; Chen Feng Qi; Dmitri I. Loukinov; Elena M. Pugacheva; Herbert C. Morse; Victor V. Lobanenkov; Elena M. Klenova; Paul E. Grundy; Andrew P. Feinberg; Anne Marie Cleton-Jansen; Elna W. Moerland; Cees J. Cornelisse; Hiroyoshi Suzuki; Akira Komiya; Annika Lindblom; Françoise Dorion-Bonnet

Tumor-associated zinc finger mutations in the CTCF transcription factor selectively alter its DNA-binding specificity

Galina N. Filippova, Jonathan E. Ulmer, James M. Moore, Michael D. Ward, Ying J. Hu, Paul E. Neiman, Steven J. Collins, Chen Feng Qi, Dmitri I. Loukinov, Elena M. Pugacheva, Herbert C. Morse, Victor V. Lobanenkov, Elena M. Klenova, Paul E. Grundy, Andrew P. Feinberg, Anne Marie Cleton-Jansen, Elna W. Moerland, Cees J. Cornelisse, Hiroyoshi Suzuki, Akira KomiyaAnnika Lindblom, Françoise Dorion-Bonnet

School of Medicine

Research output: Contribution to journal › Article › peer-review

136 Scopus citations

Abstract

CTCF is a widely expressed 11-zinc finger (ZF) transcription factor that is involved in different aspects of gene regulation including promoter activation or repression, hormone-responsive gene silencing, methylation-dependent chromatin insulation, and genomic imprinting. Because CTCF targets include oncogenes and tumor suppressor genes, we screened over 100 human tumor samples for mutations that might disrupt CTCF activity. We did not observe any CTCF mutations leading to truncations/premature stops. Rather, in breast, prostate, and Wilms’ tumors, we observed four different CTCF somatic missense mutations involving amino acids within the ZF domain. Each ZF mutation abrogated CTCF binding to a subset of target sites within the promoters/insulators of certain genes involved in regulating cell proliferation but did not alter binding to the regulatory sequences of other genes. These observations suggest that CTCF may represent a novel tumor suppressor gene that displays tumor-specific "change of function" rather than complete "loss of function".

Original language	English (US)
Pages (from-to)	48-52
Number of pages	5
Journal	Cancer Research
Volume	62
Issue number	1
State	Published - Jan 1 2002

ASJC Scopus subject areas

Oncology
Cancer Research

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Filippova, G. N., Ulmer, J. E., Moore, J. M., Ward, M. D., Hu, Y. J., Neiman, P. E., Collins, S. J., Qi, C. F., Loukinov, D. I., Pugacheva, E. M., Morse, H. C., Lobanenkov, V. V., Klenova, E. M., Grundy, P. E., Feinberg, A. P., Cleton-Jansen, A. M., Moerland, E. W., Cornelisse, C. J., Suzuki, H., ... Dorion-Bonnet, F. (2002). Tumor-associated zinc finger mutations in the CTCF transcription factor selectively alter its DNA-binding specificity. Cancer Research, 62(1), 48-52.

Filippova, GN, Ulmer, JE, Moore, JM, Ward, MD, Hu, YJ, Neiman, PE, Collins, SJ, Qi, CF, Loukinov, DI, Pugacheva, EM, Morse, HC, Lobanenkov, VV, Klenova, EM, Grundy, PE, Feinberg, AP, Cleton-Jansen, AM, Moerland, EW, Cornelisse, CJ, Suzuki, H, Komiya, A, Lindblom, A & Dorion-Bonnet, F 2002, 'Tumor-associated zinc finger mutations in the CTCF transcription factor selectively alter its DNA-binding specificity', Cancer Research, vol. 62, no. 1, pp. 48-52.

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title = "Tumor-associated zinc finger mutations in the CTCF transcription factor selectively alter its DNA-binding specificity",

abstract = "CTCF is a widely expressed 11-zinc finger (ZF) transcription factor that is involved in different aspects of gene regulation including promoter activation or repression, hormone-responsive gene silencing, methylation-dependent chromatin insulation, and genomic imprinting. Because CTCF targets include oncogenes and tumor suppressor genes, we screened over 100 human tumor samples for mutations that might disrupt CTCF activity. We did not observe any CTCF mutations leading to truncations/premature stops. Rather, in breast, prostate, and Wilms{\textquoteright} tumors, we observed four different CTCF somatic missense mutations involving amino acids within the ZF domain. Each ZF mutation abrogated CTCF binding to a subset of target sites within the promoters/insulators of certain genes involved in regulating cell proliferation but did not alter binding to the regulatory sequences of other genes. These observations suggest that CTCF may represent a novel tumor suppressor gene that displays tumor-specific {"}change of function{"} rather than complete {"}loss of function{"}.",

author = "Filippova, {Galina N.} and Ulmer, {Jonathan E.} and Moore, {James M.} and Ward, {Michael D.} and Hu, {Ying J.} and Neiman, {Paul E.} and Collins, {Steven J.} and Qi, {Chen Feng} and Loukinov, {Dmitri I.} and Pugacheva, {Elena M.} and Morse, {Herbert C.} and Lobanenkov, {Victor V.} and Klenova, {Elena M.} and Grundy, {Paul E.} and Feinberg, {Andrew P.} and Cleton-Jansen, {Anne Marie} and Moerland, {Elna W.} and Cornelisse, {Cees J.} and Hiroyoshi Suzuki and Akira Komiya and Annika Lindblom and Fran{\c c}oise Dorion-Bonnet",

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AU - Filippova, Galina N.

AU - Ulmer, Jonathan E.

AU - Moore, James M.

AU - Ward, Michael D.

AU - Hu, Ying J.

AU - Neiman, Paul E.

AU - Collins, Steven J.

AU - Qi, Chen Feng

AU - Loukinov, Dmitri I.

AU - Pugacheva, Elena M.

AU - Morse, Herbert C.

AU - Lobanenkov, Victor V.

AU - Klenova, Elena M.

AU - Grundy, Paul E.

AU - Feinberg, Andrew P.

AU - Cleton-Jansen, Anne Marie

AU - Moerland, Elna W.

AU - Cornelisse, Cees J.

AU - Suzuki, Hiroyoshi

AU - Komiya, Akira

AU - Lindblom, Annika

AU - Dorion-Bonnet, Françoise

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N2 - CTCF is a widely expressed 11-zinc finger (ZF) transcription factor that is involved in different aspects of gene regulation including promoter activation or repression, hormone-responsive gene silencing, methylation-dependent chromatin insulation, and genomic imprinting. Because CTCF targets include oncogenes and tumor suppressor genes, we screened over 100 human tumor samples for mutations that might disrupt CTCF activity. We did not observe any CTCF mutations leading to truncations/premature stops. Rather, in breast, prostate, and Wilms’ tumors, we observed four different CTCF somatic missense mutations involving amino acids within the ZF domain. Each ZF mutation abrogated CTCF binding to a subset of target sites within the promoters/insulators of certain genes involved in regulating cell proliferation but did not alter binding to the regulatory sequences of other genes. These observations suggest that CTCF may represent a novel tumor suppressor gene that displays tumor-specific "change of function" rather than complete "loss of function".

AB - CTCF is a widely expressed 11-zinc finger (ZF) transcription factor that is involved in different aspects of gene regulation including promoter activation or repression, hormone-responsive gene silencing, methylation-dependent chromatin insulation, and genomic imprinting. Because CTCF targets include oncogenes and tumor suppressor genes, we screened over 100 human tumor samples for mutations that might disrupt CTCF activity. We did not observe any CTCF mutations leading to truncations/premature stops. Rather, in breast, prostate, and Wilms’ tumors, we observed four different CTCF somatic missense mutations involving amino acids within the ZF domain. Each ZF mutation abrogated CTCF binding to a subset of target sites within the promoters/insulators of certain genes involved in regulating cell proliferation but did not alter binding to the regulatory sequences of other genes. These observations suggest that CTCF may represent a novel tumor suppressor gene that displays tumor-specific "change of function" rather than complete "loss of function".

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Tumor-associated zinc finger mutations in the CTCF transcription factor selectively alter its DNA-binding specificity

Abstract

ASJC Scopus subject areas

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