Genetic and epigenetic mutations affect the DNA binding capability of human ZFP57 in transient neonatal diabetes type 1

• Published in: FEBS letters Vol. 587; no. 10; pp. 1474 - 1481
• Main Authors: Baglivo, Ilaria, Esposito, Sabrina, De Cesare, Lucia, Sparago, Angela, Anvar, Zahra, Riso, Vincenzo, Cammisa, Marco, Fattorusso, Roberto, Grimaldi, Giovanna, Riccio, Andrea, Pedone, Paolo V.
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 21.05.2013; Elsevier Science B.V
• Subjects: Amino Acid Sequence; Animals; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cells, Cultured; Diabetes Mellitus - genetics; Diabetes Mellitus - metabolism; DNA - metabolism; DNA binding; DNA Methylation - genetics; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Embryonic Stem Cells - metabolism; Epigenesis, Genetic - genetics; Epigenesis, Genetic - physiology; Humans; Hypomethylation; Imprinting; Infant, Newborn; Infant, Newborn, Diseases - genetics; Infant, Newborn, Diseases - metabolism; Mice; Molecular Sequence Data; Mutation - physiology; Protein Binding - genetics; Repressor Proteins; Sequence Homology, Amino Acid; Transcription Factors - genetics; Transcription Factors - metabolism; Transient neonatal diabetes; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; ZFP57; Transient neonatal diabetes; Hypomethylation; ZFP57; Imprinting; DNA binding
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2013.02.045

► hZFP57 zinc finger 3 and 4 are sufficient for high affinity DNA binding. ► hZFP57 TNDM1 mutations (R248H and H277N) affect DNA binding. ► DNA sequences in the TNDM1 ICR show DNA methylation-dependent binding to hZFP57. ► mZfp57 inactivation results in loss of DNA promoter methylation and Plagl1 activation. In the mouse, ZFP57 contains three classical Cys2His2 zinc finger domains (ZF) and recognizes the methylated TGCmetCGC target sequence using the first and the second ZFs. In this study, we demonstrate that the human ZFP57 (hZFP57) containing six Cys2His2 ZFs, binds the same methylated sequence through the third and the fourth ZFs, and identify the aminoacids critical for DNA interaction. In addition, we present evidences indicating that hZFP57 mutations and hypomethylation of the TNDM1 ICR both associated with Transient Neonatal Diabetes Mellitus type 1 result in loss of hZFP57 binding to the TNDM1 locus, likely causing PLAGL1 activation.