| Identity |
| Other names | FLJ10796 |
| HGNC (Hugo) | CHFR |
| Location | 12q24.33 |
| Location_base_pair | Starts at 131927011 and ends at 131974257 bp from pter ( according to hg18-Mar_2006) [Mapping] |
| Local_order | Genes flanking CHFR in centromere to telomere direction on 12q24.33: |
| Note | CHFR functions as part of an early G2/M checkpoint. This putative early mitotic checkpoint causes a delay in chromosome condensation in response to mitotic stress. 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). 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. |
| 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/) but experimental confirmation of the genomic structure has not been reported. |
| 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. |
| Protein |
| 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. No alternative isoforms have been described to date. Domains: |
| Function | CHFR induces an early G2/M checkpoint in response to mitotic stress. 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. 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. 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. 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. However, a more recent study suggests 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. 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. The mechanistic roles of Lys63 are not understood but this type of ubiquitination is involved in error-free post-replicative DNA repair and NF-kB signal transduction. |
| 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. |
| Mutations |
| 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. |
| Implicated in |
| Disease | Lack or decreased expression of CHFR is observed in a variety of cancer cell lines and tumors. Hypermethylation of the CHFR promoter is detected in a variety of cancer cell lines including esophageal, colon, lung, osteosarcoma, central nervous system, leukemic and primary tumors of the colon, lung and esophagus suggesting that decrease or loss of expression is associated with the hypermethylation of CHFR promoter. Primary cancers of various origin (11 of 30 (37%) colon adenocarcinomas, 2 of 20 (10%) primary non-small lung carcinomas, 7 of 37 (19%) lung cancer specimens, 25 of 63 (40%) primary colorectal cancers, 27 of 51 (53%) colorectal adenomas, 16 of 54 (30%) head and neck cancers also demonstrate hypermethylation of CHFR promoter. CpG methylation and silencing of CHFR depends on the activities of two DNA methyltransferases, DNMT1 and DNMT3b since their inactivation restores CHFR expression. |
| 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. |
| Abnormal Protein | None described |
| Oncogenesis | A wide variety of cancer cell lines and tumor samples demonstrate lack of or low CHFR expression associated with abnormal checkpoint responses after treatment with nocodazole. Currently it is unclear which in vivo events trigger activation of the CHFR-associated G2/M checkpoint and which proteins interact with or regulate CHFR. The fact that nocodazole is a microtubule depolymerizing agent that can activate the checkpoint before the formation of microtubule spindles suggests that early events dependent on microtubules such as centrosome duplication and separation may be monitored by this checkpoint. |
| External links |
| Bibliography |
| Conducting the mitotic symphony. |
| Cortez D, Elledge SJ |
| Nature. 2000 ; 406 (6794) : 354-356. |
| PMID 10935617 |
| Chfr defines a mitotic stress checkpoint that delays entry into metaphase. |
| Scolnick DM, Halazonetis TD |
| Nature. 2000 ; 406 (6794) : 430-435. |
| PMID 10935642 |
| Chfr regulates a mitotic stress pathway through its RING-finger domain with ubiquitin ligase activity. |
| Chaturvedi P, Sudakin V, Bobiak ML, Fisher PW, Mattern MR, Jablonski SA, Hurle MR, Zhu Y, Yen TJ, Zhou BB |
| Cancer research. 2002 ; 62 (6) : 1797-1801. |
| PMID 11912157 |
| The checkpoint protein Chfr is a ligase that ubiquitinates Plk1 and inhibits Cdc2 at the G2 to M transition. |
| Kang D, Chen J, Wong J, Fang G |
| The Journal of cell biology. 2002 ; 156 (2) : 249-259. |
| PMID 11807090 |
| 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 ; 21 (15) : 2328-2333. |
| PMID 11948416 |
| 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 ; 23 (10) : 1695-1699. |
| PMID 12376479 |
| 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 (London, England : 1993). 2002 ; 10 (7) : 891-899. |
| PMID 12121644 |
| FHA: a signal transduction domain with diverse specificity and function. |
| Tsai MD |
| Structure (London, England : 1993). 2002 ; 10 (7) : 887-888. |
| PMID 12121642 |
| Chfr inactivation is not associated to chromosomal instability in colon cancers. |
| Bertholon J, Wang Q, Falette N, Verny C, Auclair J, Chassot C, Navarro C, Saurin JC, Puisieux A |
| Oncogene. 2003 ; 22 (55) : 8956-8960. |
| PMID 14654793 |
| 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 ; 22 (46) : 7101-7107. |
| PMID 14562038 |
| 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 ; 24 (1) : 47-51. |
| PMID 12538348 |
| 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 research. 2003 ; 63 (21) : 7185-7189. |
| PMID 14612512 |
| 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 research. 2003 ; 63 (24) : 8606-8613. |
| PMID 14695171 |
| Promotion of mitosis by activated protein kinase B after DNA damage involves polo-like kinase 1 and checkpoint protein CHFR. |
| Shtivelman E |
| Molecular cancer research : MCR. 2003 ; 1 (13) : 959-969. |
| PMID 14638868 |
| 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 |
| Proceedings of the National Academy of Sciences of the United States of America. 2003 ; 100 (13) : 7818-7823. |
| PMID 12810945 |
| CHFR-associated early G2/M checkpoint defects in breast cancer cells. |
| Erson AE, Petty EM |
| Molecular carcinogenesis. 2004 ; 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 |
| Molecular biology of the cell. 2004 ; 15 (8) : 3796-3810. |
| PMID 15146058 |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| Contributor(s) |
| Written | 06-2004 | Ayse E Erson, Elizabeth M Petty |
| Biology Department, Room: 141, Middle East Technical University, Ankara 06531, Turkey |
| Citation |
| This paper should be referenced as such : |
| Erson AE, Petty EM . CHFR (Checkpoint with fork-head associated and ring finger). Atlas Genet Cytogenet Oncol Haematol. June 2004 . URL : http://AtlasGeneticsOncology.org/Genes/CHFRID526.html |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Sat Feb 6 13:40:09 CET 2010 |
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