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

More general terms

• E3 ubiquitin ligase
• zinc finger protein
• phosphoprotein

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=55743
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:55743
• OMIM: https://mirror.omim.org/entry/605209
• UniProt: http://www.uniprot.org/uniprot/Q96EP1.html