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FLASH GENE

Symbol

CHFR

contributors: mct - updated : 25-01-2015

HGNC name	checkpoint with forkhead and ring finger domains
HGNC id	20455

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	47.27 kb     18 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_018223 18 - 3168 NP_060693 69 623 - 2000 10935642 isoform 4 NM_001161344 18 - 3291 NP_001154816 - 664 - 2000 10935642 isoform 1 NM_001161345 18 - 3288 NP_001154817 - 663 - 2000 10935642 isoform 2 NM_001161346 18 - 3255 NP_001154818 - 652 - 2000 10935642 isoform 3 NM_001161347 16 - 3015 NP_001154819 - 572 - 2000 10935642 isoform 5

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive liver       moderately Lymphoid/Immune spleen       highly   thymus       highly Nervous nerve cranial nerve     highly Reproductive male system prostate     moderately Respiratory respiratory tract trachea     highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / Hematopoietic bone marrow

cell lineage

cell lines

fluid/secretion

at STAGE

cell cycle

cell cycle, G1, S

Text	weakly expressed in G1, higlhy in S phase

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal FHA domain (forkhead associated domain)
	a C3HC4 type (RING) zinc finger in the N terminus
	a central RING finger domain
	a cysteine-rich domain that is the essential domain for the CHFR/MAD2L1 interaction and for promoting interaction between MAD2L1 and CDC20 to inhibit the anaphase-promoting complex
	a PBZ motif, needed for the interaction with polyADP-ribose
	C-terminal cysteine-rich (CR) regio

HOMOLOGY

interspecies	homolog to murine Chfr (80.7pc)
	homolog to rattus Chfr (81.3pc)

Homologene

FAMILY

CHFR family

CATEGORY

tumor suppressor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,cytoskeleton,microtubule,mitotic spindle
	intracellular,nucleus
text	colocalizes with TPT1 to the mitotic spindle

basic FUNCTION	mediating protein-protein interactions
	defining a checkpoint that delays entry into metaphase in response to mitotic stress
	acting as an ubiquitin ligase (ubiquitinating Plk1)
	inhibiting Cdc2 at the G2 to M transition
	tumor suppressor controlling the expression of key mitotic proteins such STK6
	E3 ubiquitin ligase and early mitotic checkpoint protein implicated in many cancers and in the maintenance of genomic stability
	role for CHFR regulating chromosome segregation where decreased expression, as seen in cancer cells, contributes to genomic instability by impairing the spindle assembly checkpoint
	checkpoint protein that plays an important function in cell cycle progression and tumor suppression
	plays a role in the maintenance of genome integrity
	promotes the ubiquitination of AURKA and PLK1
	may also promote the formation of 'Lys-63'-linked polyubiquitins chains and functions with the specific ubiquitin conjugating UBEN2-UBE2V2 heterodimer
	negative regulator of the NF-KappaB pathway, downregulating IL8 production
	binding and downregulating HDAC1 by inducing its polyubiquitination
	functions as a mitotic checkpoint by delaying entry into metaphase in response to mitotic stress
	plays an important role in regulation of HLTF stability and protects cells against HLTF-mediated cell migration
	critical role for CHFR in the MAD2L1 spindle checkpoint
	is one of the E3 ligases, which is known to be a tumor suppressor and play an essential role in cell cycle control and tumorigenesis
	CHFR and RNF8 may have overlapping targets and/or functions in mitosis
	RNF8 and CHFR affect chromatin relaxation and modulate ATM activation and DNA damage response pathways
	RNF8 and CHFR, function together to activate ATM and maintain genomic stability
	mediates the ubiquitination of the major components of the SWI/SNF complex (PMID;
	PARP1 is a novel CHFR binding protein and found a functional interaction that regulates the early mitotic checkpoint and tumorigenesis
	is an important E3 ligase in the early stage of the DNA damage response, which mediates the crosstalk between
	important role in cell cycle progression and tumorigenesis
	new regulatory mechanism for CHFR that sequential post-translational modifications of CHFR by SUMO and ubiquitin coordinately regulates its stability
	ubiquitin ligase CHFR, that is a checkpoint protein involved in G2/M transition, and a new effector involved in the control of insulin-induced cell proliferation

CELLULAR PROCESS	cell cycle, division, mitosis
	cell cycle, checkpoint
	protein, degradation

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

INTERACTION

DNA

RNA

small molecule	metal binding, other,
	phosphotyrosine
	ion zinc Zn2+

protein	interacting with STK6
	interacting with KIF22 and controling genomic stability
	interacting with TPT1 (CHFR-TPT1 interaction is stable throughout the cell cycle, but it could be diminished by the complete depolymerization of the microtubules, providing a possible mechanism where CHFR could be the sensor that detects microtubule disruption and then activates the prophase checkpoint)
	interacts with the mitotic kinase Aurora A to regulate its expression
	MAD2L1 is a novel CHFR interacting protein
	interacting with HDAC1
	interacting with HDAC2, PML
	HLTF is a CHFR-interacting protein (CHFR binds to and ubiquitinates HLTF, leading to its degradation)
	interact with MAD2L1, an important component of the spindle assembly checkpoint, where CHFR knockdown resulted in mislocalization of MAD2L1 and disruption of the MAD2L1/CDC20 interaction
	CHFR interacts with SMARCA4, SMARCB1, and SMARCD1 of the SWI/SNF-like BAF complex and ubiquitinates them to target for degradation through a proteasome-mediated pathway, and SMARCC1 stabilizes these components by blocking their interaction with CHFR
	SMARCA4, SMARCB1, and SMARCD1, but not SMARCC1, are the substrates of CHFR for ubiquitination
	tumor suppressor, regulating the ubiquitination and degradation of the SWI/SNF chromatin remodeling proteins
	PARP1 is a novel CHFR binding protein suggesting a functional interaction that regulates the early mitotic checkpoint and tumorigenesis (CHFR polyubiquitinates PARP1 and caused cell cycle arrest via PARP1 degradation)
	aggregated LDL (agLDL) prolongs the half life of LRP1 by preventing the receptor ubiquitinylation, at least in part, through CHFR targeting
	ubiquitinates and regulates PBK levels, which is essential for its checkpoint function
	PBK and PTEN are new players in CHFR mediated mitotic checkpoint
	CHFR is a partner of the molecular adapter GRB14, an inhibitor of insulin signalling

cell & other

REGULATION

inhibited by

phosphorylation

Other	CpG methylation-dependent silencing of CHFR expression in cancers
	polyADPribosylated
	autoubiquitinated
	is covalently modified by SUMO-1 at lysine 663 and subsequently destabilized by ubiquitin-proteasome system (emerging role of SUMOylation in modulating protein stability)

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral         3 of 8 human cancer cell lines examined did not contain CHFR mRNA tumoral     --low   by aberrant methylation associated with gene silencing in primary hepatocellular carcinomas, oral squamous cell carcinomas , gastric cancer , and ovarian cancer constitutional     --low   led to disorganized multipolar mitotic spindles

Susceptibility

Variant & Polymorphism

Candidate gene	molecular marker to estimate the malignancy of hepatocellular carcinoma
Marker
Therapy target
	System Type Disorder Pubmed cancer     CHFR-mediated downregulation of HLTF may help protect against cancer

ANIMAL & CELL MODELS