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E3 ubiquitin-protein ligase CHFR; checkpoint with forkhead & RING finger domains protein; RING finger protein 196 (CHFR, RNF196)

Function: - E3 ubiquitin-protein ligase - functions in the antephase checkpoint by actively delaying passage into mitosis in response to microtubule poisons - acts in early prophase before chromosome condensation, when the centrosomes move apart along the periphery of the nucleus - probably involved in signaling the presence of mitotic stress caused by microtubule poisons by mediating Lys-48- linked ubiquitination of target proteins, leading to their degradation by the proteasome - promotes ubiquitination & subsequent degradation of AURKA & PLK1 - probably acts as a tumor suppressor, possibly by mediating polyubiquitination of HDAC1, leading to its degradation - may also promote formation of Lys-63-linked polyubiquitin chains & functions with the specific ubiquitin-conjugating UBC13-MMS2 (UBE2N-UBE2V2) heterodimer - substrates polyubiquitinated at Lys-63 are usually not targeted for degradation, but are rather involved in signaling cellular stress - protein modification; protein ubiquitination - poly-ADP-ribosylated - in addition to binding non covalently poly(ADP-ribose) via its PBZ-type Zn+2 finger, the protein is also covalently poly-ADP-ribosylated by PARP1 - autoubiquitinated; may regulate its cellular level - phosphorylated upon DNA damage, probably by ATM or ATR - phosphorylated by PKB - phosphorylation may affect its E3 ligase activity - interacts with HDAC1 & HDAC2 - interacts with PML (with sumoylated form of PML) Structure: - the PBZ-type Zn+2 finger (CYR) mediates non- covalent poly(ADP-ribose)-bindin. g - poly(ADP-ribose)-binding is dependent on the presence of Zn+2 & is required for its function in antephase checkpoint - the FHA domain plays a key role in the anti-proliferative properties of the protein & is involved in initiating a cell cycle arrest at G2/M - FHA domain may be required to interact with phosphorylated proteins - belongs to the CHFR family - contains 1 FHA domain - contains 1 PBZ-type Zn+2 finger - contains 1 RING-type Zn+2 finger Compartment: nucleus, PML body Alternative splicing: named isoforms=5 Expression: - ubiquitous - weakly expressed in G1 phase - highly expressed during S phase Pathology: - CHFR is silenced in many primary cancers because of CpG methylation & deacetylated histones on its promoter region; this raises the question of whether CHFR silencing is a consequence or a cause of primary cancers

General

phosphoprotein E3 ubiquitin ligase; ubiquitin-ligating enzyme E3; N end-recognizing protein zinc finger protein

Properties

SIZE: entity length = 664 aa MW = 73 kD COMPARTMENT: cell nucleus MOTIF: forkhead-associated (FHA) domain {38-89} Thr phosphorylation site {T130} RING-finger {304-343} EFFECTOR-BOUND: Zn+2 FOR-BINDING-OF: DNA motif Thr phosphorylation site {T386} Zinc finger NAME: Zinc finger SITE: 633-655 EFFECTOR-BOUND: Zn+2

Database Correlations

OMIM 605209 UniProt Q96EP1 Pfam PF00498 Entrez Gene 55743 Kegg hsa:55743

References

  1. UniProt :accession Q96EP1
  2. Atlas of Genetics & Cytogenetics in Oncology & Haematology http://atlasgeneticsoncology.org/genes/CHFRID526.html