ICBP90, an E2F-1 target, recruits HDAC1 and binds to methyl-CpG through its SRA domain

Abstract

ICBP90, inverted CCAAT box-binding protein of 90 kDa, has been reported as a regulator of topoisomerase IIa expression. We present evidence here that ICBP90 binds to methyl-CpG when at least one symmetrically methylated-CpG dinucleotides is presented as its recognition sequence. A SET and RING finger-associated (SRA) domain accounts for the high binding affinity of ICBP90 for methyl-CpG dinucleotides. This protein constitutes a complex with HDAC1 also via its SRA domain, and bound to methylated promoter regions of various tumor suppressor genes, including p16INK4A and p14 ARF , in cancer cells. It has been reported that expression of ICBP90 was upregulated by E2F-1, and we confirmed that the upregulation was caused by binding of E2F-1 to the intron1 of ICBP90, which contains two E2F-1-binding motifs. Our data also revealed accumulation of ICBP90 in breast-cancer cells, where it might suppress expression of tumor suppressor genes through deacetylation of histones after recruitment of HDAC1. The data reported here suggest that ICBP90 is involved in cell proliferation by way of methylation-mediated regulation of certain genes.

UHRF1‐mediated tumor suppressor gene inactivation in nonsmall cell lung cancer

“…Although UHRF1 promoter bears a CpG island, no DNA methylation was found in normal or tumor tissue, excluding the possibility of an epigenetic expression feedback loop. As UHRF1 is a known E2F1 target, 29,45 we also examined E2F1 mRNA expression levels in this sample set. Indeed, a strong relationship was observed between the expression levels of the 2 genes, supporting the concept that UHRF1 regulation is under the control of the pRb/E2F1pathway.…”

“…29 UHRF1-knockout mouse embryonic stem cells exhibit significant loss of genomic methylation. 25 The UHRF1 gene is a target for the transcriptional activator E2F1, 29 expression is associated with increased cell proliferation. 30,31 Accumulating evidence suggests that UHRF1 has a putative oncogene function.…”

Two missense variants in UHRF1BP1 are independently associated with systemic lupus erythematosus in Hong Kong Chinese

“…18 Despite its unknown function, the sequence of this protein is highly conserved through evolution; the human protein has a 91% sequence identity to that of horse, and 82 and 83% similarity to those in rat and mouse, respectively, and 75 and 61% to those in opossum and chicken, respectively. For Q454R encoded by rs11755393, the position is not well conserved through evolution and neither are its surrounding amino acid residues.…”

Induction of apoptosis by thymoquinone in lymphoblastic leukemia Jurkat cells is mediated by a p73-dependent pathway which targets the epigenetic integrator UHRF1

“…In this point of view, accumulating evidences have shown that UHRF1 acts as a multi-modular protein involved in the maintenance of the chromatin status and its propagation during cell division. Indeed, UHRF1 binds to methylated DNA and recruits DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1) through the SRA (SET and RING finger Associated) domain [13,[16][17][18][19]. These protein-protein interactions precede S phase entry and could be required for cell cycle progression [10,20].…”