Alternative titles; symbolsCYCLOSPORIN A-ASSOCIATED HELICASE-LIKE PROTEIN; CAHLHGNC Approved Gene Symbol: YTHDC2Cytogenetic location: 5q22.2 Genomic coordina...
Alternative titles; symbols
HGNC Approved Gene Symbol: YTHDC2
Cytogenetic location: 5q22.2 Genomic coordinates (GRCh38): 5:113,513,682-113,595,283 (from NCBI)
YTHDC2 belongs to the DExD/H-box family of ATP-dependent RNA helicases. Members of this family function in RNA processing and metabolism, including transcription, alternative splicing, and degradation (summary by Tanabe et al., 2014).
▼ Cloning and Expression
Cyclosporin A (CsA) is a natural compound with multiple biologic activities, including immunosuppression, antichaperone activity, inhibition of transporters, and antiviral activity. Using immobilized CsA to capture CsA-binding proteins, followed by mass spectrometric analysis, database analysis, and amplification from human liver total RNA, Morohashi et al. (2011) cloned YTHDC2, which they called CAHL. The deduced 1,430-amino acid protein has an N-terminal R3H domain, followed by a DExHc-type helicase domain, an ankyrin (see 612641) domain, a HELICc domain, an HA2 region, and a C-terminal YTH domain. RT-PCR detected highest CAHL expression in testis, with lower expression in intestine, kidney, heart, and thymus, and little to no expression in other tissues. CAHL expression was detected in all human tumor cell lines examined. Fluorescence-tagged CAHL was expressed in endoplasmic reticulum.
Using immunofluorescence analysis, Jain et al. (2018) found that Ythdc2 localized to cytoplasm of mouse prophase I sperm cells.
▼ Gene Structure
Tanabe et al. (2014) determined that the promoter region of the YTHDC2 gene has a CpG island that overlaps a cAMP response element. It also has GATA (see 305371)- and AP1 (see 165160)-binding sites.
Fanale et al. (2014) reported that the YTHDC2 gene maps to chromosome 5q22.2.
Jain et al. (2018) reported that the mouse Ythdc2 gene maps to chromosome 18.
▼ Gene Function
Using mutation analysis, Morohashi et al. (2011) determined that the C-terminal region of CAHL bound CsA. This C-terminal region of CAHL showed RNA-dependent ATP hydrolysis, which was suppressed by CsA in a dose-dependent manner. CAHL expression was upregulated by TNF-alpha (TNF; 191160), but not by other proinflammatory cytokines. Knockdown of CAHL expression in a human liver cell line reduced replication of hepatitis C virus (HCV; see 609532). In contrast, overexpression of CAHL increased HCV replication in a dose-dependent manner. CAHL formed a complex with HCV-derived RNA polymerase NS5B and host-derived cyclophilin B (CYPB; 123841). Knockdown of CAHL caused dissociation of CYPB from the NS5B-RNA complex.
Tanabe et al. (2014) found that knockdown of YTHDC2 reduced growth and anchorage-independent colony formation in Huh7 human hepatocellular carcinoma cells. TNF stimulation of Huh7 cells resulted in binding of phosphorylated JUN (165160) and ATF2 (123811) to a cAMP response element in the YTHDC2 promoter, concomitant with YTHDC2 upregulation.
▼ Molecular Genetics
By analyzing DNA samples of peripheral leukocytes from 72 patients with sporadic pancreatic adenocarcinoma (see 260350), Fanale et al. (2014) identified copy number variation (CNV) in the region of chromosome 5 harboring YTHDC2. This region showed a deletion of 1 allele in 50% of the patients, but not in controls. Furthermore, 82.6% of Sicilian patients showed germline loss of 1 allele.
▼ Animal Model
In a mutagenesis screen, Jain et al. (2018) identified a mouse mutant, termed 'ketu,' that resulted from a his327-to-arg mutation in Ythdc2. Both male and female homozygous ketu mice were sterile. In ketu male mice, undifferentiated germ cell divisions occurred normally, but entry into and progression through meiosis was defective, as the chromosomes condensed prematurely and germ cells underwent programmed cell death. This cell death accounted for the hypogonadism, absence of postmeiotic cells in adults, and sterility of ketu mice. Further analysis showed that ketu germ cells were defective at transitioning to the meiotic RNA expression program. The phenotype observed in ketu mice was similar to that of mice lacking Meioc (616934), a partner of Ythdc2. The authors proposed that YTHDC2 and MEIOC function together to regulate germ cell development around the time of meiotic entry.