Tumor-associated zinc finger mutations in the CTCF transcription factor selectively alter tts DNA-binding specificity.
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."
Filippova
Galina N
GN
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Qi
Chen-Feng
CF
Ulmer
Jonathan E
JE
Moore
James M
JM
Ward
Michael D
MD
Hu
Ying J
YJ
Loukinov
Dmitri I
DI
Pugacheva
Elena M
EM
Klenova
Elena M
EM
Grundy
Paul E
PE
Feinberg
Andrew P
AP
Cleton-Jansen
Anne-Marie
AM
Moerland
Elna W
EW
Cornelisse
Cees J
CJ
Suzuki
Hiroyoshi
H
Komiya
Akira
A
Lindblom
Annika
A
Dorion-Bonnet
Françoise
F
Neiman
Paul E
PE
Morse
Herbert C
HC
Collins
Steven J
SJ
Lobanenkov
Victor V
VV
D000595:Amino Acid Sequence; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D016147:Genes, Tumor Suppressor; D005914:Globins / Q000235:genetics; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009113:Muramidase / Q000235:genetics; D020125:Mutation, Missense; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D012097:Repressor Proteins; D013379:Substrate Specificity; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D009396:Wilms Tumor / Q000235:genetics / Q000378:metabolism; D016335:Zinc Fingers / Q000235:genetics*
D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D005914:Globins; D009113:Muramidase