62
edits
Changes
→Gene Overview
==Gene Overview==
==Gene Overview==
''TET2'' is a member of the ten-eleven translocation (TET) family along with ''TET1'' and ''TET3'' (Lorsbach et al., 2003). The TET family proteins play key roles in DNA cytosine demethylation. All family members share a C-terminal catalytic double-stranded β-helix dioxygenase domain which has oxidating activity against 5-methylcytosine (5-mC). This domain also has binding sites for α-ketoglutarate (αKG) and Fe(II) which are required for its catalytic function. The middle portion of the TET protein is a cysteine-rich domain with unknown function.
The N-terminal region of TET1 and TET3 contain a conserved CXXC-type domain that is critical for binding to unmethylated cytosine residues, but TET2 lacks this domain. It is hypothesised that the CXXC-type domain of TET2 separated during evolution to become the CXXC-containing gene ''IDAX'', which is located at the 5’ end of TET2 in the opposite orientation. IDAX can apparently negatively regulate TET2 (Ko et al., 2013).
Cytosine residue methylation mediated by DNA methyltransferase (''DNMT'') is an important mechanism for gene expression regulation (Wu and Zhang, 2014). TET family proteins demethylate cytosine residues by converting 5-mC to 5-hydroxymetylcytosine (5-hmC). Methylation is then removed either by “passive dilution”, whereby methylation status is not replicated onto the newly synthesised DNA strand after DNA replication, or after further processing by TET proteins or other enzymes which allow base excision DNA repair to convert the residue back into cytosine (Wu and Zhang, 2014).
TET family proteins also interact with O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) to facilitate chromatin modification, another important regulator of gene transcription (Chen et al., 2013). The TET-OGT interaction augments OGT activity resulting in enhanced O-GlcNAcylation of target proteins such as histone 2B (H2B) and host cell factor 1 (HCF1), and also recruits OGT directly to the transcriptional start sites of certain target genes (Deplus et al., 2013; Vella et al., 2013).
Mouse studies demonstrate that ''TET2'' plays a critical role in the regulation of haematopoiesis by controlling stem and progenitor cell homeostasis (Quivoron et al., 2011). Evidence suggests that ''TET2'' functions as a tumour suppressor in mice and humans (Quivoron et al., 2011).
Most ''TET2'' mutations in human cancers are missense mutations in the C-terminal catalytic domain or nonsense/frameshift mutations that cause truncation of the protein upstream of the catalytic domain (Cimmino et al., 2011). This mutational pattern is consistent with the role of ''TET2'' as a tumour suppressor.
In mouse models ''TET2'' homozygous mutations result in multipotent progenitor cell and myeloid progenitor cell expansion, enhanced haematopoietic stem cell (HSC) self-renewal, and disruption of myeloid differentiation (Kunimoto et al., 2012). These phenotypes are recapitulated by ''TET2'' haploinsufficiency, suggesting that heterozygous mutations are sufficient to impair haematopoiesis (Moran-Crusio et al., 2011). There is interplay between ''TET2'' and the TCA cycle genes ''IDH1'' and ''IDH2'' (Figueroa et al., 2010). IDH1 and IDH2 produce αKG which is required for TET2 function.
''TET2'' mutations are found most often in haematological malignancies, where they appear to be early genetic events (Pan et al., 2015). Somatic ''TET2'' mutations are recurrent in otherwise healthy elderly individuals as part of a process called clonal haematopoiesis of indeterminate potential, or CHIP (Busque et al., 2012; Solary et al., 2014; Steensma et al., 2015). TET2 also appears to play roles in other cancers, but evidence is more limited.
==Common Alteration Types==
==Common Alteration Types==