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CHFR: a key checkpoint component implicated in a wide range of cancers

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Abstract

CHFR (Checkpoint with Forkhead-associated and RING finger domains) has been implicated in a checkpoint regulating entry into mitosis. However, the details underlying its roles and regulation are unclear due to conflicting lines of evidence supporting different notions of its functions. We provide here an overview of how CHFR is thought to contribute towards regulating mitotic entry and present possible explanations for contradictory observations published on the functions and regulation of CHFR. Furthermore, we survey key data showing correlations between promoter hypermethylation or down-regulation of CHFR and cancers, with a view on the likely reasons why different extents of correlations have been reported. Lastly, we explore the possibilities of exploiting CHFR promoter hypermethylation status in diagnostics and therapeutics for cancer patients. With keen interest currently focused on the association between hypermethylation of CHFR and cancers, details of how CHFR functions require further study to reveal how its absence might possibly contribute to tumorigenesis.

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Acknowledgments

We thank the anonymous reviewer for his constructive suggestions to improve the review. YFM is funded by the Singapore Ministry of Education grant R183-000-246-112 and the Yong Loo Ling SoM cross-department grant R183-000-288-733.

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  1. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, MD7, 8 Medical Drive, Singapore, 117597, Singapore

    Sheru Sanbhnani & Foong May Yeong

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  1. Sheru Sanbhnani
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Correspondence to Foong May Yeong.

Glossary of terms

Glossary of terms

  • Antephase—refers to the time in late G2 phase when signs of chromosome condensation first become visible until commitment to mitosis [6].

  • ATM—refers to Ataxia telangiectasia mutated, which is a key checkpoint kinase that plays a role the activation of the DNA damage checkpoint (reviewed in [3, 4]). It is important for a cell to respond to radiation-induced double-strand breaks by eliciting cell cycle delay and repair of the DNA breaks.

  • ATR—refers to Ataxia telangiectasia mutated- and Rad3-related that is another major component of the DNA damage and replication checkpoints (reviewed in [5]). ATR is activated in the presence of DNA damage and replication blocks. Similar to ATM, activation of ATR leads to triggering of cell cycle delay and repair of the DNA damage.

  • CIN—refers to Chromosome Instability. CIN relates to a persistent high rate of chromosome loss or gain due to mis-segregation of chromosomes during cell division (reviewed in [113]). This usually leads to aneuploidy in the resulting cells and is thought to contribute to tumorigenesis.

  • DNA mis-match repair system—The system consists of proteins that are involved in repair of errors made due to mis-incorporation of nucleotides during the process DNA replication (reviewed in [70]). Such activities help to keep mutation rates low in dividing cells.

  • FHA domain—Fork-head associated domain refers to the phosphothreonine-binding domain that is found in a range of proteins with diverse functions [114]. The domain functions essentially to monitor the status phosphorylation of specific threonine residues found in target proteins. The FHA domain is quite common in proteins that are involved in DNA damage response pathways.

  • Microsatellite—refers to tandem mono-, di-, tri- and tetranucleotide repeats (e.g., A n or (CA) that are distributed in our genome [115]. The correction of errors in the microsatellite depends upon the DNA mis-match repair system [70].

  • Mitotic index—This refers to the fraction of the total number of cells examined that show condensed chromosomes [7, 8].

  • MSI—Microsatellite instability refers to the errors associated with microsatellites that fail to be (reviewed in [71, 75]).

  • MSS—Microsatellite stable refers to the absence of MSI [71].

  • RING-finger (RF) domain—RING stands for Really Interesting New Gene. The RING-finger domain is a type of Zinc Finger domain that is a small motif that folds around one or more zinc ions [116]. The RING-finger domain is found in ubiquitin ligases such as the E3 ligases that are important for ubiquitin-mediated destruction of proteins.

  • Ubiquitin and E3 ubiquitin ligase—Ubiquitin is a ubiquitous polypeptide with 76-amino acid residues (reviewed in [18]). It is activated by ATP by the action of a ubiquitin-activating enzyme known as E1. The ubiquitin is then transferred to a ubiquitin-conjugating enzyme known as E2. The E3 ubiquitin ligase is needed to help the E2 enzyme attach the ubiquitin to target proteins. Ubiquitin is attached to lysine residues on target proteins. If several ubiquitins are added to a single lysyl residue on the target protein, the target protein is referred to as poly-ubiquitinated. In some instances, ubiquitin is added to several distinct lysine residues on a target protein. In such cases, it is referred to as multi-ubiquitination.

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Sanbhnani, S., Yeong, F.M. CHFR: a key checkpoint component implicated in a wide range of cancers. Cell. Mol. Life Sci. 69, 1669–1687 (2012). https://doi.org/10.1007/s00018-011-0892-2

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  • DOI: https://doi.org/10.1007/s00018-011-0892-2

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