Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

CHFR (Checkpoint with fork-head associated and ring finger)

Written2004-06Ayse E Erson, Elizabeth M Petty
Departments of Human Genetics and Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA (EMP)
Updated2014-12Ayse E Erson-Bensan, Hesna Begum Akman, Elizabeth M Petty
Department of Biology, Middle East Technical University, Ankara, Turkey (AEEB, HBA); University of Wisconsin School of Medicine, Public Health, Madison, WI 53705-2221, USA (EMP)

Abstract Growing evidence in mice, primary human tumors, and mammalian cell culture models indicate that CHFR may function as a potent tumor suppressor. CHFR functions as part of an early G2/M checkpoint, more specifically in antephase. Antephase refers to late G2 when chromosome condensation starts. This early mitotic checkpoint causes a delay in chromosome condensation in response to mitotic stresses. The human CHFR gene was originally identified during a search for novel cell cycle checkpoint proteins that have fork-head associated domains. Initial analysis indicated that the CHFR-associated G2/M checkpoint was inactivated in a subset of cancers as demonstrated by high mitotic indices (a high percentage of cells that have condensed chromosomes) in response to exposure to the microtubule poison, nocodazole, due to lack of CHFR expression or CHFR mutations in various cancers. Many other studies showed promoter hypermethylation leading to low/no expression of CHFR.

Keywords CHFR, cell cycle, checkpoint, antephase

(Note : for Links provided by Atlas : click)

Identity

Alias_namescheckpoint with forkhead and ring finger domains
checkpoint with forkhead and ring finger domains, E3 ubiquitin protein ligase
Alias_symbol (synonym)FLJ10796
RNF196
Other alias
HGNC (Hugo) CHFR
LocusID (NCBI) 55743
Atlas_Id 526
Location 12q24.33  [Link to chromosome band 12q24]
Location_base_pair Starts at 132840352 and ends at 132887618 bp from pter ( according to hg19-Feb_2009)  [Mapping CHFR.png]
Local_order Genes flanking CHFR in centromere to telomere direction on 12q24.33:
Peroxisomal membrane protein 2 gene (PXMP2) --- Hypothetical protein gene (MGC5352) --- Golgi autoantigen, golgin subfamily a3 gene (GOLGA3) --- Checkpoint with FHA and RING finger gene (CHFR) --- Hypothetical gene (GeneID: 90462) --- Zinc finger protein 26 gene (ZNF26)
Fusion genes
(updated 2016)
ARF3 (12q13.12) / CHFR (12q24.33)CHFR (12q24.33) / OSBPL8 (12q21.2)GOLGA3 (12q24.33) / CHFR (12q24.33)
POMGNT2 (3p22.1) / CHFR (12q24.33)ZNF605 (12q24.33) / CHFR (12q24.33)
Note CHFR functions as part of an early G2/M checkpoint, more specifically in antephase. Antephase refers to late G2 when chromosome condensation starts. This early mitotic checkpoint causes a delay in chromosome condensation in response to mitotic stresses. The human CHFR gene was originally identified during a search for novel cell cycle checkpoint proteins that have fork-head associated domains. Initial analysis indicated that the CHFR-associated G2/M checkpoint was inactivated in a subset of cancers as demonstrated by high mitotic indices (a high percentage of cells that have condensed chromosomes) in response to exposure to the microtubule poison, nocodazole, due to lack of CHFR expression or CHFR mutations in a neuroblastoma, an osteosarcoma and 2 colon cancer cell lines (4 of 8 different cancer cell lines) (Scolnick and Halazonetis, 2000). Various further studies demonstrated loss of or low CHFR expression in various types of cancer cells including those from colon, esophageal, gastric, lung and breast cancers. Over time, CHFR has been identified as an inactivated tumor suppressor protein in a diverse group of solid tumor malignancies, mostly as demonstrated by promoter CpG island methylation.

DNA/RNA

Description The CHFR gene spans approximately 47 kb and has at least 18 exons (BC012072 vs. NT_024477) as predicted according to Spidey (http://www.ncbi.nlm.nih.gov/spidey/) http://www.ncbi.nlm.nih.gov/spidey/). While multiple splice forms have been demonstrated (Toyota et al, 2003), the genomic structure has not been experimentally confirmed.
Transcription CHFR mRNA is 3189 bp (BC012072). Transcripts that lack exon 2, exon 5 and exon 6 have been detected in various tissues including bone marrow, small intestine, lung, heart, testis, kidney, stomach and lympocytes as well as some cancer cell lines by RT-PCR. Northern blot transcript analysis suggests that limited if any alternative splicing is present in most fetal and adult tissues where CHFR is expressed a prominent 3.2 kb is observed. CHFR mRNA is detected in heart, brain, placenta, lung, liver, muscle, kidney, pancreas by Northern blot analysis (Scolnick and Halazonetis, 2000).
Alternative mRNA transcripts lacking specific exons (2, 5, and/or 6) have been described for CHFR (Toyota et al. 2003) The isoform that lacks exon 2 happens to lack the FHA domain and was also found to be highly expressed in cancer cells when compared to normal samples .
Pseudogene No known pseudogene has been reported

Protein

 
  Domains of CHFR. The forkhead-associated domain of CHFR is located at the N-terminus. RING-finger domain with the ubiquitination activity is located through 303-346 amino acids. Poly-ADP-ribose binding zinc finger motif overlaps with the cystein-rich region near the C-terminus.
Description CHFR encodes a 652 amino acid protein (according to BC012072 nucleotide sequence) with FHA (forkhead associated), RING (really interesting new gene) finger and cysteine rich domains. Cysteine rich region further harbors a PBZ domain. No alternative isoforms have been described to date.

Domains:

  • FHA domains (16-123) are present in cell cycle checkpoint genes, transcription factors, protein kinases and have roles in protein-protein interactions with specificity for phosphorylated targets. The three dimensional structure of CHFR suggests that CHFR may be able to recognize as of yet unidentified phosphorylated targets targets (Stavridi et al., 2002; Tsai 2002)..
  • RING finger domains are found in ubiquitin ligases. Ubiquitin ligases attach ubiquitin to target proteins during a cascade of enzymatic reactions. RING finger domains are present in a variety of proteins (e.g. Anaphase promoting complex, APC, Cbl family proteins, MDM2) implicated in cancer.
  • Cys: Cystein-rich region (476-641)
  • PBZ: poly-ADP-ribose binding zinc finger motif (620-644) is at the C terminus. PBZ domain allows CHFR to bind to poly (ADP-ribose). This domain is generally required for the activity of checkpoint response proteins (Ahel et al., 2008)
  • Expression CHFR is ubiquitiously expressed in normal fetal and adult human tissues. Protein levels are predicted to fluctuate during the cell cycle possibly through auto-ubiquitination based on overexpression studies in cancer cell lines (Chaturverdi et al., 2002; Kim et al., 2011). Upon mitotic stresses, CHFR protein levels are thought to be stabilized and reaching the highest levels at G2/M.
    Localisation Various lines of evidence suggest different cellular localizations for CHFR. Endogenous and low ectopic expression of CHFR showed cytoplasm and spindle localization patterns during mitosis. Higher expression of ectopic CHFR correlated with a shift in the localization to the nucleus (Burgess et al., 2008). Later on, nuclear presence of CHFR was explained via a short lysine-rich stretch (KKK) at amino acid residues 257-259 (Kwon et al., 2009).
    Egeberg et al., 2012 suggested a centrosome/primary cilium axis localization of CHFR. CHFR was also shown to localize to the mitotic spindle by an interaction with TCTP, a protein involved in microtubule stabilization and ?-tubulin (Kim, 2011)
    Function Initially, CHFR was described to induce an early G2/M checkpoint in response to mitotic stress (Scolnick and Halozenetis, 2000). Cell lines expressing wild-type CHFR exhibit low mitotic index (percentage of cells with condensed chromosomes) and delayed entry into metaphase when centrosome separation is inhibited by mitotic stress. In contrast, cancer cell lines lacking CHFR function enter metaphase without delay and demonstrate higher mitotic indices compared to the CHFR expressing cell lines. (Erson and Petty, 2004).

    In vitro studies suggest that the RING finger domain in CHFR also facilitates ubiquitin ligase function and that it is essential for checkpoint function of CHFR (Chaturved et al., 2002).. In vitro Xenopus extract experiments suggested that CHFR specifically targets PLK1 (polo-like kinase 1) for degradation when extracts are supplemented with high ubiquitin concentrations (Kang, 2002). Thus, according to this in vitro model, CHFR is able to halt cell cycle progression early in mitosis by degrading PLK1, a major player for the activation of mitosis promoting factor. In addition, AURORA A is known to phosphorylate and activate PLK1 as well as CDC25B eventually driving CYCLIN B/CDK1 activation. Interestingly, CHFR was also found to bind via its cysteine rich C-region and ubiquitinate AURORA A, leading to its degradation (Yu et al., 2005). The auto-ubiquitylation ability of CHFR at G2 Phase was proposed to be required for the accumulation of Plk1 and mitotic entry in mammalian cells (Kim et al., 2011). Earlier, Oh et al., showed deubiquitination of Chfr, by USP7/HAUSP (deubiquitinating enzyme) also to regulate its own stability and activity (Oh et al,. 2007).

    On the contrary, Summers et al. suggested PLK1 and AURORA A levels not to change when CHFR was expressed in HCT116 cells treated with Nocodazole (Summers et al., 2005).

    More recently, other proteins including TOPK and PTEN have been shown to play a role in the CHFR related mitotic spindle checkpoing (Shinde et al. 2013)

    Furthermore, Bothos et al., showed that CHFR was able to activate the p38 stress kinase pathway, which reverses chromosome condensation and induces a mitotic arrest and suggested that the ubiquitin ligase function of CHFR may be different than the current in vitro model and that instead of Lys48 ubiquitination, CHFR may link ubiquitin to target protein or proteins via Ly63 due to its interaction with the heteromeric ubiquitin conjugating enzyme complex, Ubc13-Mms2 (Bothos et al., 2003). In the canonical ubiquitin/proteasome pathway, Lys48 is a signal for degradation of target proteins whereas Lys63 ubiquitination functions as a non-proteolytic tag for protein targets. Lys63 ubiquitination is thought to be involved in DNA repair mechanisms. Indeed, CHFR appears to have important roles in DNA damage response (Shtivelman et al., 2003). CHFR and RNF8 (A ubiquin ligase) ubiquitinate histones (H2A and H2B) upon ioinizing radiation (Al-Hakim et al., 2010; Wu et al., 2011). These ubiquitinations seem to be important for the eventual activation of the key DNA damage checkpoint effector, ATM (Derks et al., 2006; Lavin and Kozlov, 2007). Recently, CHFR was reported to interact with MAD2, an important component of the spindle assembly checkpoint. CHFR knockdown resulted in mislocalization of MAD2 and disruption of the MAD2/CDC20 interaction. The cysteine-rich region of CHFR appears to be the essential domain for the CHFR/MAD2 interaction and for promoting interaction between MAD2 and CDC20 to inhibit the anaphase-promoting complex (Privette et al., 2008; Keller and Petty, 2011).

    Homology M.musculus 5730484M20Rik RIKEN cDNA 5730484M20 gene, R.norvegicus LOC288734 similar to RIKEN cDNA 5730484M20, budding yeast proteins, Dma1 and Dma2 are 58% identical to each other and are possible homologs of human CHFR. Dma1 and Dma2 have roles in spindle formation and formation of septin ring during cytokinesis (Fraschini et al., 2004).

    Mutations

    Epigenetics Hypermethylation of the CHFR promoter has been the most commonly reported mechanism lowering CHFR expression observed in tumors (Privitte and Petty, 2008).
    Germinal No germline mutations have been reported yet.
    Somatic A panel of 53 lung carcinomas has been screened with matching normal tissue and 3 mutations were found, one of which was associated with loss of heterozygosity. Mutations found in patient samples were: C587T, G695C (both between the FHA and RING domains) and T1697C (in the C-terminal cysteine rich region of CHFR). However, no correlation was found with a specific diagnosis or stage of the disease in the patients (Mariatos et al., 2003). No clear pathogenic mutations in the CHFR coding sequence have been observed in the analysis of tumors (Privette and Petty, 2008).

    Implicated in

    Note
      
    Entity Gastric cancer
    Note In gastric cancer, methylation of CHFR promoter is highly recurrent (Hu et al., 2011; Li et al., 2014; Satoh et al., 2003). Decreased CHFR expression has been shown in 20% of gastric cell lines and 39% of primary gastric cancers tested (Satoh et al., 2003). In a study with 102 paraffin-embedded gastric cancer samples, 34% of samples showed methylation. No association was found between methylation of CHFR promoter with gender, age, tumor size, tumor differentiation, and lymph node metastasis. According to Cox proportional hazards model in docetaxel-treated gastric cancer patients, resistance to docetaxel was found in CHFR unmethylated patients. CHFR methylation may serve as a docetaxel-sensitive marker in human gastric cancer (Li et al., 2014).
      
      
    Entity Lung cancer
    Note Loss of detectable CHRF levels has been linked to aberrant hypermethylation in lung cancer (Mizuno et al., 2002). Apart from hypermethylation, inactivation of CHFR gene by missense mutations is reported for lung carcinomas (Mariatos et al., 2003). In a study with 165 lung carcinomas, 10% were found to have hypermethylated CHFR promoter. In addition,
    Prognosis CHFR hypermethylation was significantly correlated with poor prognosis of lung carcinomas, suggesting a therapeutic potential for CHFR targeted approaches (Koga et al., 2013).
    Cytogenetics A lung cancer patient sample demonstrates loss of heterozygosity for a CA repeat located on a BAC that contains the CHFR gene. Several other cancers demonstrate allelic imbalance involving chromosome band 12q24 but specific analysis of CHFR in these samples has not been investigated.
      
      
    Entity Breast cancer
    Note An initial screening resulted with 50% of 24 breast cancer cell lines to have CHFR expression (Erson and Petty, 2004). CHFR protein levels were also low in 36% of breast cancer patients. Lack of CHFR expression in primary cancers was associated with increased tumor size and estrogen receptor negativity (Privette et al., 2007). In another study, 110 primary breast cancers were investigated for methylation status, only 0.9% showed hypermethylation of CHFR promoter (Tokunaga et al., 2006). Although hypermethylation of CHFR promoter is common in various cancers, this study showed it to be a rare event in primary breast carcinomas. Moreover, an interaction between CHFR and PARP-1 was shown to have an important role in cell cycle regulation. CHFR, by its E3 ubiquitin ligase function, caused degradation of PARP-1, which lead to cell cycle arrest in prophase. These findings suggested a novel potential therapeutic approach for combinational chemotherapy with PARP inhibitors for breast cancer cells (Kashima et al., 2012).
      
      
    Entity Leukemia
    Note Methylation of CHFR promoter was detected in 39% of leukemia patients. CHFR hypermethylation incidence was shown to be unchanged between acute myelocytic leukemia and acute lymphocytic leukemia (Gong et al., 2005).
      
      
    Entity Esophageal cancer
    Note When expression level of CHFR was investigated, 4 out of 15 esophageal cancer cell lines (26.7%) and 7 out of 43 (16.3%) primary esophageal cancers showed loss of CHFR expression due to hypermethylation of promoter (Shibata et al., 2002). In another study, CHFR transcript was found to be downregulated in 79% of esophageal adenocarcinomas (44 of 56 samples) compared to 41 normal samples. Immunohistochemical analysis also correlated with expression analysis, 75% (56 of 75) of samples showed either weak or no immunostaining. Hypermethylation of promoter correlated with low CHFR expression in esophageal cancer patients; 31% of samples (18 of 58) displayed significant hypermethylation (Soutto et al., 2010). Another recent study used 40 esophageal squamous cell carcinoma patient samples for RT-qPCR analysis of CHFR expression. Aberrant hypermethylation of the CHFR promoter was observed in 13 of 29 primary esophageal cancers. The CHFR expression levels of the methylated samples was significantly lower than that of the unmethylated samples (Suzuki et al., 2014)
      
      
    Entity Hepatocellular carcinoma
    Note Aberrant methylation was detected in 22 of 65 (35%) primary hepatocellular carcinomas (HCC), compared to noncancerous liver cells (Sakai et al., 2005). Also, methylation of CHFR was found to be significantly correlated with advanced disease stage (p=0.037) and an infiltrated growth pattern (p=0.047). In another study with 70 HCC samples, methylation frequency of CHFR was 43% (30 out of 70) (Li et al., 2012). 5-aza-2'-deoxycytidine (5-aza-dC) treatment of HCC cell lines restored expression of CHFR.
      
      
    Entity Prostate cancer
    Note In a genome profiling study, blood and bone-marrow samples of prostate cancer patients were investigated using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) (Schwarzenbach et al., 2011). MS-MLPA detected genetic and epigenetic aberrations of 37 tumor suppressor genes including CHFR.
      
      
    Entity Head and neck cancer
    Note 19% of 126 head and neck cancer patients showed methylation of a group of tumor suppressors. CHFR was one of the most frequently methylated genes in tumor tissue compared to normal (Yalniz et al., 2011).
      
      
    Entity Cervical cancer
    Note Out of 14 cervical adenocarcinoma specimens tested by methylation-specific PCR, 2 of them (12.3%) showed aberrant methylation of CHFR (Banno et al., 2007). When six cell lines derived from human cervical carcinoma were analyzed, hypermethylaton of CHFR was observed in HeLa and SKG-IIIb cells. In another study, sequential methylation of eight genes including CHFR was linked to HPV-induced cervical carcinogenesis (Henken et al., 2007).
      

    Bibliography

    Poly(ADP-ribose)-binding zinc finger motifs in DNA repair/checkpoint proteins
    Ahel I, Ahel D, Matsusaka T, Clark AJ, Pines J, Boulton SJ, West SC
    Nature 2008 Jan 3;451(7174):81-5
    PMID 18172500
     
    The ubiquitous role of ubiquitin in the DNA damage response
    Al-Hakim A, Escribano-Diaz C, Landry MC, O'Donnell L, Panier S, Szilard RK, Durocher D
    DNA Repair (Amst) 2010 Dec 10;9(12):1229-40
    PMID 21056014
     
    Epigenetic inactivation of the CHFR gene in cervical cancer contributes to sensitivity to taxanes
    Banno K, Yanokura M, Kawaguchi M, Kuwabara Y, Akiyoshi J, Kobayashi Y, Iwata T, Hirasawa A, Fujii T, Susumu N, Tsukazaki K, Aoki D
    Int J Oncol 2007 Oct;31(4):713-20
    PMID 17786301
     
    The Chfr mitotic checkpoint protein functions with Ubc13-Mms2 to form Lys63-linked polyubiquitin chains
    Bothos J, Summers MK, Venere M, Scolnick DM, Halazonetis TD
    Oncogene 2003 Oct 16;22(46):7101-7
    PMID 14562038
     
    Chfr interacts and colocalizes with TCTP to the mitotic spindle
    Burgess A, Labbé JC, Vigneron S, Bonneaud N, Strub JM, Van Dorsselaer A, Lorca T, Castro A
    Oncogene 2008 Sep 18;27(42):5554-66
    PMID 18504434
     
    CHFR promoter methylation indicates poor prognosis in stage II microsatellite stable colorectal cancer
    Cleven AH, Derks S, Draht MX, Smits KM, Melotte V, Van Neste L, Tournier B, Jooste V, Chapusot C, Weijenberg MP, Herman JG, de Bruïne AP, van Engeland M
    Clin Cancer Res 2014 Jun 15;20(12):3261-71
    PMID 24928946
     
    Frequent hypermethylation of the 5' CpG island of the mitotic stress checkpoint gene Chfr in colorectal and non-small cell lung cancer
    Corn PG, Summers MK, Fogt F, Virmani AK, Gazdar AF, Halazonetis TD, El-Deiry WS
    Carcinogenesis 2003 Jan;24(1):47-51
    PMID 12538348
     
    Promoter methylation precedes chromosomal alterations in colorectal cancer development
    Derks S, Postma C, Moerkerk PT, van den Bosch SM, Carvalho B, Hermsen MA, Giaretti W, Herman JG, Weijenberg MP, de Bruïne AP, Meijer GA, van Engeland M
    Cell Oncol 2006;28(5-6):247-57
    PMID 17167178
     
    Primary cilia and aberrant cell signaling in epithelial ovarian cancer
    Egeberg DL, Lethan M, Manguso R, Schneider L, Awan A, Jørgensen TS, Byskov AG, Pedersen LB, Christensen ST
    Cilia 2012 Aug 10;1(1):15
    PMID 23351307
     
    CHFR-associated early G2/M checkpoint defects in breast cancer cells
    Erson AE, Petty EM
    Mol Carcinog 2004 Jan;39(1):26-33
    PMID 14694445
     
    Functional characterization of Dma1 and Dma2, the budding yeast homologues of Schizosaccharomyces pombe Dma1 and human Chfr
    Fraschini R, Bilotta D, Lucchini G, Piatti S
    Mol Biol Cell 2004 Aug;15(8):3796-810
    PMID 15146058
     
    Deficiencies in Chfr and Mlh1 synergistically enhance tumor susceptibility in mice
    Fu Z, Regan K, Zhang L, Muders MH, Thibodeau SN, French A, Wu Y, Kaufmann SH, Lingle WL, Chen J, Tindall DJ
    J Clin Invest 2009 Sep;119(9):2714-24
    PMID 19690386
     
    Methylation of gene CHFR promoter in acute leukemia cells
    Gong H, Liu W, Zhou J, Xu H
    J Huazhong Univ Sci Technolog Med Sci 2005;25(3):240-2
    PMID 16201259
     
    Sequential gene promoter methylation during HPV-induced cervical carcinogenesis
    Henken FE, Wilting SM, Overmeer RM, van Rietschoten JG, Nygren AO, Errami A, Schouten JP, Meijer CJ, Snijders PJ, Steenbergen RD
    Br J Cancer 2007 Nov 19;97(10):1457-64
    PMID 17971771
     
    Pathobiologic implications of methylation and expression status of Runx3 and CHFR genes in gastric cancer
    Hu SL, Huang DB, Sun YB, Wu L, Xu WP, Yin S, Chen J, Jiang XD, Shen G
    Med Oncol 2011 Jun;28(2):447-54
    PMID 20300977
     
    CHFR protein regulates mitotic checkpoint by targeting PARP-1 protein for ubiquitination and degradation
    Kashima L, Idogawa M, Mita H, Shitashige M, Yamada T, Ogi K, Suzuki H, Toyota M, Ariga H, Sasaki Y, Tokino T
    J Biol Chem 2012 Apr 13;287(16):12975-84
    PMID 22337872
     
    CHFR binds to and regulates MAD2 in the spindle checkpoint through its cysteine-rich domain
    Keller JA, Petty EM
    Biochem Biophys Res Commun 2011 Jun 10;409(3):389-93
     
    The auto-ubiquitylation of E3 ubiquitin-protein ligase Chfr at G2 phase is required for accumulation of polo-like kinase 1 and mitotic entry in mammalian cells
    Kim JS, Park YY, Park SY, Cho H, Kang D, Cho H
    J Biol Chem 2011 Sep 2;286(35):30615-23
     
    CHFR aberrant methylation involves a subset of human lung adenocarcinoma associated with poor clinical outcomes
    Koga T, Takeshita M, Ijichi K, Yano T, Maehara Y, Sueishi K
    Hum Pathol 2013 Jul;44(7):1382-90
    PMID 23415374
     
    Nuclear localization of Chfr is crucial for its checkpoint function
    Kwon YE, Kim YS, Oh YM, Seol JH
    Mol Cells 2009 Mar 31;27(3):359-63
    PMID 19326084
     
    ATM activation and DNA damage response
    Lavin MF, Kozlov S
    Cell Cycle 2007 Apr 15;6(8):931-42
    PMID 17457059
     
    Predictive value of CHFR and MLH1 methylation in human gastric cancer
    Li Y, Yang Y, Lu Y, Herman JG, Brock MV, Zhao P, Guo M
    Gastric Cancer 2015 Apr;18(2):280-7
    PMID 24748501
     
    Promoter hypermethylation of DNA damage response genes in hepatocellular carcinoma
    Li Z, Zhang H, Yang J, Hao T, Li S
    Cell Biol Int 2012 May 1;36(5):427-32
    PMID 21864295
     
    Inactivating mutations targeting the chfr mitotic checkpoint gene in human lung cancer
    Mariatos G, Bothos J, Zacharatos P, Summers MK, Scolnick DM, Kittas C, Halazonetis TD, Gorgoulis VG
    Cancer Res 2003 Nov 1;63(21):7185-9
    PMID 14612512
     
    Aberrant hypermethylation of the CHFR prophase checkpoint gene in human lung cancers
    Mizuno K, Osada H, Konishi H, Tatematsu Y, Yatabe Y, Mitsudomi T, Fujii Y, Takahashi T
    Oncogene 2002 Apr 4;21(15):2328-33
    PMID 11948416
     
    CHFR: A Novel Mitotic Checkpoint Protein and Regulator of Tumorigenesis
    Privette LM, Petty EM
    Transl Oncol 2008 Jul;1(2):57-64
    PMID 18633460
     
    Aberrant methylation of the CHFR gene in advanced hepatocellular carcinoma
    Sakai M, Hibi K, Kanazumi N, Nomoto S, Inoue S, Takeda S, Nakao A
    Hepatogastroenterology 2005 Nov-Dec;52(66):1854-7
    PMID 16334792
     
    Epigenetic inactivation of CHFR and sensitivity to microtubule inhibitors in gastric cancer
    Satoh A, Toyota M, Itoh F, Sasaki Y, Suzuki H, Ogi K, Kikuchi T, Mita H, Yamashita T, Kojima T, Kusano M, Fujita M, Hosokawa M, Endo T, Tokino T, Imai K
    Cancer Res 2003 Dec 15;63(24):8606-13
    PMID 14695171
     
    Genomic profiling of cell-free DNA in blood and bone marrow of prostate cancer patients
    Schwarzenbach H, Chun FK, Isbarn H, Huland H, Pantel K
    J Cancer Res Clin Oncol 2011 May;137(5):811-9
    PMID 20683729
     
    Chfr defines a mitotic stress checkpoint that delays entry into metaphase
    Scolnick DM, Halazonetis TD
    Nature 2000 Jul 27;406(6794):430-5
    PMID 10935642
     
    Chfr expression is downregulated by CpG island hypermethylation in esophageal cancer
    Shibata Y, Haruki N, Kuwabara Y, Ishiguro H, Shinoda N, Sato A, Kimura M, Koyama H, Toyama T, Nishiwaki T, Kudo J, Terashita Y, Konishi S, Sugiura H, Fujii Y
    Carcinogenesis 2002 Oct;23(10):1695-9
    PMID 12376479
     
    TOPK and PTEN participate in CHFR mediated mitotic checkpoint
    Shinde SR, Gangula NR, Kavela S, Pandey V, Maddika S
    Cell Signal 2013 Dec;25(12):2511-7
    PMID 24012691
     
    Promotion of mitosis by activated protein kinase B after DNA damage involves polo-like kinase 1 and checkpoint protein CHFR
    Shtivelman E
    Mol Cancer Res 2003 Nov;1(13):959-69
    PMID 14638868
     
    Epigenetic and genetic silencing of CHFR in esophageal adenocarcinomas
    Soutto M, Peng D, Razvi M, Ruemmele P, Hartmann A, Roessner A, Schneider-Stock R, El-Rifai W
    Cancer 2010 Sep 1;116(17):4033-42
    PMID 20564104
     
    Crystal structure of the FHA domain of the Chfr mitotic checkpoint protein and its complex with tungstate
    Stavridi ES, Huyen Y, Loreto IR, Scolnick DM, Halazonetis TD, Pavletich NP, Jeffrey PD
    Structure 2002 Jul;10(7):891-9
    PMID 12121644
     
    The CHFR mitotic checkpoint protein delays cell cycle progression by excluding Cyclin B1 from the nucleus
    Summers MK, Bothos J, Halazonetis TD
    Oncogene 2005 Apr 14;24(16):2589-98
    PMID 15674323
     
    Epigenetic silencing of checkpoint with fork-head associated and ring finger gene expression in esophageal cancer
    Suzuki Y, Miyagi Y, Yukawa N, Rino Y, Masuda M
    Oncol Lett 2014 Jan;7(1):69-73
    PMID 24348823
     
    Alternative efficacy-predicting markers for paclitaxel instead of CHFR in non-small-cell lung cancer
    Takeshita M, Koga T, Takayama K, Yano T, Maehara Y, Nakanishi Y, Sueishi K
    Cancer Biol Ther 2010 Nov 1;10(9):933-41
    PMID 20855974
     
    Aberrant hypermethylation of the promoter region of the CHFR gene is rare in primary breast cancer
    Tokunaga E, Oki E, Nishida K, Koga T, Yoshida R, Ikeda K, Kojima A, Egashira A, Morita M, Kakeji Y, Maehara Y
    Breast Cancer Res Treat 2006 May;97(2):199-203
    PMID 16502017
     
    Epigenetic inactivation of CHFR in human tumors
    Toyota M, Sasaki Y, Satoh A, Ogi K, Kikuchi T, Suzuki H, Mita H, Tanaka N, Itoh F, Issa JP, Jair KW, Schuebel KE, Imai K, Tokino T
    Proc Natl Acad Sci U S A 2003 Jun 24;100(13):7818-23
    PMID 12810945
     
    FHA: a signal transduction domain with diverse specificity and function
    Tsai MD
    Structure 2002 Jul;10(7):887-8
    PMID 12121642
     
    Association between CHFR methylation and chemosensitivity of paclitaxel in advanced gastric cancer
    Wang M, Shen L, Deng D
    Med Oncol 2014 Apr;31(4):907
    PMID 24639283
     
    Chfr and RNF8 synergistically regulate ATM activation
    Wu J, Chen Y, Lu LY, Wu Y, Paulsen MT, Ljungman M, Ferguson DO, Yu X
    Nat Struct Mol Biol 2011 Jun 26;18(7):761-8
    PMID 21706008
     
    Simultaneous methylation profiling of tumor suppressor genes in head and neck cancer
    Yalniz Z, Demokan S, Suoglu Y, Ulusan M, Dalay N
    DNA Cell Biol 2011 Jan;30(1):17-24
    PMID 20860434
     
    Chfr is required for tumor suppression and Aurora A regulation
    Yu X, Minter-Dykhouse K, Malureanu L, Zhao WM, Zhang D, Merkle CJ, Ward IM, Saya H, Fang G, van Deursen J, Chen J
    Nat Genet 2005 Apr;37(4):401-6
    PMID 15793587
     

    Citation

    This paper should be referenced as such :
    Erson-Bensan AE, Akman HB, Petty EM
    CHFR (Checkpoint with fork-head associated and ring finger);
    Atlas Genet Cytogenet Oncol Haematol. in press
    On line version : http://AtlasGeneticsOncology.org/Genes/CHFRID526.html
    History of this paper:
    Erson, AE ; Petty, EM. CHFR (checkpoint with fork-head associated, ring finger). Atlas Genet Cytogenet Oncol Haematol. 2004;8(3):208-210.
    http://documents.irevues.inist.fr/bitstream/handle/2042/38099/06-2004-CHFRID526.pdf


    External links

    Nomenclature
    HGNC (Hugo)CHFR   20455
    Cards
    AtlasCHFRID526
    Entrez_Gene (NCBI)CHFR  55743  checkpoint with forkhead and ring finger domains
    AliasesRNF116; RNF196
    GeneCards (Weizmann)CHFR
    Ensembl hg19 (Hinxton)ENSG00000072609 [Gene_View]
    Ensembl hg38 (Hinxton)ENSG00000072609 [Gene_View]  chr12:132840352-132887618 [Contig_View]  CHFR [Vega]
    ICGC DataPortalENSG00000072609
    TCGA cBioPortalCHFR
    AceView (NCBI)CHFR
    Genatlas (Paris)CHFR
    WikiGenes55743
    SOURCE (Princeton)CHFR
    Genetics Home Reference (NIH)CHFR
    Genomic and cartography
    GoldenPath hg38 (UCSC)CHFR  -     chr12:132840352-132887618 -  12q24.33   [Description]    (hg38-Dec_2013)
    GoldenPath hg19 (UCSC)CHFR  -     12q24.33   [Description]    (hg19-Feb_2009)
    EnsemblCHFR - 12q24.33 [CytoView hg19]  CHFR - 12q24.33 [CytoView hg38]
    Mapping of homologs : NCBICHFR [Mapview hg19]  CHFR [Mapview hg38]
    OMIM605209   
    Gene and transcription
    Genbank (Entrez)AF170724 AK001658 AK027687 AK054917 AK090948
    RefSeq transcript (Entrez)NM_001161344 NM_001161345 NM_001161346 NM_001161347 NM_018223
    RefSeq genomic (Entrez)
    Consensus coding sequences : CCDS (NCBI)CHFR
    Cluster EST : UnigeneHs.720197 [ NCBI ]
    CGAP (NCI)Hs.720197
    Alternative Splicing GalleryENSG00000072609
    Gene ExpressionCHFR [ NCBI-GEO ]   CHFR [ EBI - ARRAY_EXPRESS ]   CHFR [ SEEK ]   CHFR [ MEM ]
    Gene Expression Viewer (FireBrowse)CHFR [ Firebrowse - Broad ]
    SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
    GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)55743
    GTEX Portal (Tissue expression)CHFR
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtQ96EP1   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
    NextProtQ96EP1  [Sequence]  [Exons]  [Medical]  [Publications]
    With graphics : InterProQ96EP1
    Splice isoforms : SwissVarQ96EP1
    PhosPhoSitePlusQ96EP1
    Domaine pattern : Prosite (Expaxy)FHA_DOMAIN (PS50006)    ZF_RING_1 (PS00518)    ZF_RING_2 (PS50089)   
    Domains : Interpro (EBI)FHA_dom    SMAD_FHA_domain    Znf_RING    Znf_RING/FYVE/PHD    Znf_RING_CS   
    Domain families : Pfam (Sanger)FHA (PF00498)   
    Domain families : Pfam (NCBI)pfam00498   
    Domain families : Smart (EMBL)FHA (SM00240)  RING (SM00184)  
    Conserved Domain (NCBI)CHFR
    DMDM Disease mutations55743
    Blocks (Seattle)CHFR
    PDB (SRS)1LGP    1LGQ    2XOC    2XOY    2XOZ    2XP0   
    PDB (PDBSum)1LGP    1LGQ    2XOC    2XOY    2XOZ    2XP0   
    PDB (IMB)1LGP    1LGQ    2XOC    2XOY    2XOZ    2XP0   
    PDB (RSDB)1LGP    1LGQ    2XOC    2XOY    2XOZ    2XP0   
    Structural Biology KnowledgeBase1LGP    1LGQ    2XOC    2XOY    2XOZ    2XP0   
    SCOP (Structural Classification of Proteins)1LGP    1LGQ    2XOC    2XOY    2XOZ    2XP0   
    CATH (Classification of proteins structures)1LGP    1LGQ    2XOC    2XOY    2XOZ    2XP0   
    SuperfamilyQ96EP1
    Human Protein AtlasENSG00000072609
    Peptide AtlasQ96EP1
    IPIIPI00023513   IPI00953641   IPI00930659   IPI00796680   IPI00397548   IPI01016023   IPI00973335   IPI01011351   IPI01011932   IPI01012291   
    Protein Interaction databases
    DIP (DOE-UCLA)Q96EP1
    IntAct (EBI)Q96EP1
    FunCoupENSG00000072609
    BioGRIDCHFR
    STRING (EMBL)CHFR
    ZODIACCHFR
    Ontologies - Pathways
    QuickGOQ96EP1
    Ontology : AmiGOnucleotide binding  protein polyubiquitination  ubiquitin-protein transferase activity  protein binding  nucleus  ubiquitin-dependent protein catabolic process  mitotic cell cycle checkpoint  mitotic cell cycle checkpoint  zinc ion binding  PML body  modification-dependent protein catabolic process  positive regulation of protein ubiquitination  protein destabilization  positive regulation of proteasomal ubiquitin-dependent protein catabolic process  cell division  ubiquitin protein ligase activity  
    Ontology : EGO-EBInucleotide binding  protein polyubiquitination  ubiquitin-protein transferase activity  protein binding  nucleus  ubiquitin-dependent protein catabolic process  mitotic cell cycle checkpoint  mitotic cell cycle checkpoint  zinc ion binding  PML body  modification-dependent protein catabolic process  positive regulation of protein ubiquitination  protein destabilization  positive regulation of proteasomal ubiquitin-dependent protein catabolic process  cell division  ubiquitin protein ligase activity  
    NDEx NetworkCHFR
    Atlas of Cancer Signalling NetworkCHFR
    Wikipedia pathwaysCHFR
    Orthology - Evolution
    OrthoDB55743
    GeneTree (enSembl)ENSG00000072609
    Phylogenetic Trees/Animal Genes : TreeFamCHFR
    HOVERGENQ96EP1
    HOGENOMQ96EP1
    Homologs : HomoloGeneCHFR
    Homology/Alignments : Family Browser (UCSC)CHFR
    Gene fusions - Rearrangements
    Fusion : MitelmanARF3/CHFR [12q13.12/12q24.33]  [t(12;12)(q13;q24)]  
    Fusion : MitelmanCHFR/OSBPL8 [12q24.33/12q21.2]  [t(12;12)(q21;q24)]  
    Fusion : MitelmanGOLGA3/CHFR [12q24.33/12q24.33]  [t(12;12)(q24;q24)]  
    Fusion: TCGAARF3 12q13.12 CHFR 12q24.33 LUAD
    Fusion: TCGACHFR 12q24.33 OSBPL8 12q21.2 BRCA
    Fusion: TCGAGOLGA3 12q24.33 CHFR 12q24.33 LUSC
    Polymorphisms : SNP and Copy number variants
    NCBI Variation ViewerCHFR [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)CHFR
    dbVarCHFR
    ClinVarCHFR
    1000_GenomesCHFR 
    Exome Variant ServerCHFR
    ExAC (Exome Aggregation Consortium)CHFR (select the gene name)
    Genetic variants : HAPMAP55743
    Genomic Variants (DGV)CHFR [DGVbeta]
    DECIPHERCHFR [patients]   [syndromes]   [variants]   [genes]  
    CONAN: Copy Number AnalysisCHFR 
    Mutations
    ICGC Data PortalCHFR 
    TCGA Data PortalCHFR 
    Broad Tumor PortalCHFR
    OASIS PortalCHFR [ Somatic mutations - Copy number]
    Somatic Mutations in Cancer : COSMICCHFR  [overview]  [genome browser]  [tissue]  [distribution]  
    Mutations and Diseases : HGMDCHFR
    LOVD (Leiden Open Variation Database)Whole genome datasets
    LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
    LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
    BioMutasearch CHFR
    DgiDB (Drug Gene Interaction Database)CHFR
    DoCM (Curated mutations)CHFR (select the gene name)
    CIViC (Clinical Interpretations of Variants in Cancer)CHFR (select a term)
    intoGenCHFR
    NCG5 (London)CHFR
    Cancer3DCHFR(select the gene name)
    Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
    Diseases
    OMIM605209   
    Orphanet
    MedgenCHFR
    Genetic Testing Registry CHFR
    NextProtQ96EP1 [Medical]
    TSGene55743
    GENETestsCHFR
    Target ValidationCHFR
    Huge Navigator CHFR [HugePedia]
    snp3D : Map Gene to Disease55743
    BioCentury BCIQCHFR
    ClinGenCHFR
    Clinical trials, drugs, therapy
    Chemical/Protein Interactions : CTD55743
    Chemical/Pharm GKB GenePA134898949
    Clinical trialCHFR
    Miscellaneous
    canSAR (ICR)CHFR (select the gene name)
    Probes
    Litterature
    PubMed90 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    CoreMineCHFR
    EVEXCHFR
    GoPubMedCHFR
    iHOPCHFR
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

    Search in all EBI   NCBI

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Mon May 22 09:07:46 CEST 2017

    Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

    For comments and suggestions or contributions, please contact us

    jlhuret@AtlasGeneticsOncology.org.