| Structural highlights
Function
CHFR_HUMAN E3 ubiquitin-protein ligase that 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 centrosome move apart from each other along the periphery of the nucleus. Probably involved in signaling the presence of mitotic stress caused by microtubule poisons by mediating the 'Lys-48'-linked ubiquitination of target proteins, leading to their degradation by the proteasome. Promotes the ubiquitination and subsequent degradation of AURKA and PLK1. Probably acts as a tumor suppressor, possibly by mediating the polyubiquitination of HDAC1, leading to its degradation. May also promote the formation of 'Lys-63'-linked polyubiquitin chains and functions with the specific ubiquitin-conjugating UBC13-MMS2 (UBE2N-UBE2V2) heterodimer. Substrates that are polyubiquitinated at 'Lys-63' are usually not targeted for degradation, but are rather involved in signaling cellular stress.[1] [2] [3] [4] [5] [6] [7]
Evolutionary Conservation
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Publication Abstract from PubMed
Cellular stress in early mitosis activates the antephase checkpoint, resulting in the decondensation of chromosomes and delayed mitotic progression. Checkpoint with forkhead-associated and RING domains (CHFR) is central to this checkpoint, and its activity is ablated in many tumors and cancer cell lines through promoter hypermethylation or mutation. The interaction between the PAR-binding zinc finger (PBZ) of CHFR and poly(ADP-ribose) (PAR) is crucial for a functional antephase checkpoint. We determined the crystal structure of the cysteine-rich region of human CHFR (amino acids 425-664) to 1.9 A resolution, which revealed a multizinc binding domain of elaborate topology within which the PBZ is embedded. The PBZ of CHFR closely resembles the analogous motifs from aprataxin-like factor and CG1218-PA, which lie within unstructured regions of their respective proteins. Based on co-crystal structures of CHFR bound to several different PAR-like ligands (adenosine 5'-diphosphoribose, adenosine monophosphate, and P(1)P(2)-diadenosine 5'-pyrophosphate), we made a model of the CHFR-PAR interaction, which we validated using site-specific mutagenesis and surface plasmon resonance. The PBZ motif of CHFR recognizes two adenine-containing subunits of PAR and the phosphate backbone that connects them. More generally, PBZ motifs may recognize different numbers of PAR subunits as required to carry out their functions.
Structural basis of poly(ADP-ribose) recognition by the multizinc binding domain of checkpoint with forkhead-associated and RING Domains (CHFR).,Oberoi J, Richards MW, Crumpler S, Brown N, Blagg J, Bayliss R J Biol Chem. 2010 Dec 10;285(50):39348-58. Epub 2010 Sep 29. PMID:20880844[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Scolnick DM, Halazonetis TD. Chfr defines a mitotic stress checkpoint that delays entry into metaphase. Nature. 2000 Jul 27;406(6794):430-5. PMID:10935642 doi:10.1038/35019108
- ↑ Kang D, Chen J, Wong J, Fang G. The checkpoint protein Chfr is a ligase that ubiquitinates Plk1 and inhibits Cdc2 at the G2 to M transition. J Cell Biol. 2002 Jan 21;156(2):249-59. Epub 2002 Jan 21. PMID:11807090 doi:10.1083/jcb.200108016
- ↑ Chaturvedi P, Sudakin V, Bobiak ML, Fisher PW, Mattern MR, Jablonski SA, Hurle MR, Zhu Y, Yen TJ, Zhou BB. Chfr regulates a mitotic stress pathway through its RING-finger domain with ubiquitin ligase activity. Cancer Res. 2002 Mar 15;62(6):1797-801. PMID:11912157
- ↑ Bothos J, Summers MK, Venere M, Scolnick DM, Halazonetis TD. The Chfr mitotic checkpoint protein functions with Ubc13-Mms2 to form Lys63-linked polyubiquitin chains. Oncogene. 2003 Oct 16;22(46):7101-7. PMID:14562038 doi:10.1038/sj.onc.1206831
- ↑ Erson AE, Petty EM. CHFR-associated early G2/M checkpoint defects in breast cancer cells. Mol Carcinog. 2004 Jan;39(1):26-33. PMID:14694445 doi:10.1002/mc.10161
- ↑ Ahel I, Ahel D, Matsusaka T, Clark AJ, Pines J, Boulton SJ, West SC. Poly(ADP-ribose)-binding zinc finger motifs in DNA repair/checkpoint proteins. Nature. 2008 Jan 3;451(7174):81-5. doi: 10.1038/nature06420. PMID:18172500 doi:10.1038/nature06420
- ↑ Oh YM, Kwon YE, Kim JM, Bae SJ, Lee BK, Yoo SJ, Chung CH, Deshaies RJ, Seol JH. Chfr is linked to tumour metastasis through the downregulation of HDAC1. Nat Cell Biol. 2009 Mar;11(3):295-302. doi: 10.1038/ncb1837. Epub 2009 Feb 1. PMID:19182791 doi:10.1038/ncb1837
- ↑ Oberoi J, Richards MW, Crumpler S, Brown N, Blagg J, Bayliss R. Structural basis of poly(ADP-ribose) recognition by the multizinc binding domain of checkpoint with forkhead-associated and RING Domains (CHFR). J Biol Chem. 2010 Dec 10;285(50):39348-58. Epub 2010 Sep 29. PMID:20880844 doi:10.1074/jbc.M110.159855
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