RNA methyltransferase is responsible for transferring methyl and resulting in methylation on the bases or ribose ring of RNA, which existed widely but mostly remains an open question. A recombinant protein PH1948 predicting RNA methyltransferase from Pyrococcus horikoshii OT3 has been crystallized. The crystals of selenomethionyl PH1948 belong to space group C2, with unit-cell parameters a=207.0 A, b=43.1 A, c=118.2 A, b=92.1 degrees , and diffract X-rays to 2.2 A resolution. The V(M) value was determined to be 2.8 A3/Da, indicating the presence of four protein molecules in the asymmetric unit.
Crystallization ; methods ; Molecular Conformation ; Pyrococcus horikoshii ; enzymology ; X-Ray Diffraction ; tRNA Methyltransferases ; analysis ; chemistry

Accumulating evidence has confirmed the links between transfer RNA (tRNA) modifications and tumor progression. The present study is the first to explore the role of tRNA methyltransferase 5 (TRMT5), which catalyzes the m1G37 modification of mitochondrial tRNAs in hepatocellular carcinoma (HCC) progression. Here, based on bioinformatics and clinical analyses, we identified that TRMT5 expression was upregulated in HCC, which correlated with poor prognosis. Silencing TRMT5 attenuated HCC proliferation and metastasis both in vivo and in vitro, which may be partially explained by declined extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Mechanistically, we discovered that knockdown of TRMT5 inactivated the hypoxia-inducible factor-1 (HIF-1) signaling pathway by preventing HIF-1α stability through the enhancement of cellular oxygen content. Moreover, our data indicated that inhibition of TRMT5 sensitized HCC to doxorubicin by adjusting HIF-‍1α. In conclusion, our study revealed that targeting TRMT5 could inhibit HCC progression and increase the susceptibility of tumor cells to chemotherapy drugs. Thus, TRMT5 might be a carcinogenesis candidate gene that could serve as a potential target for HCC therapy.
Humans ; Carcinoma, Hepatocellular/pathology* ; Cell Hypoxia ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Liver Neoplasms/pathology* ; Signal Transduction/genetics* ; tRNA Methyltransferases/metabolism*

OBJECTIVETo study the associations of single nucleotide polymorphisms (SNPs) of TCF7L2, CDKAL1, SLC30A8, HHEX with diabetic retinopathy (DR) and nephropathy (DN) in type 2 diabetes mellitus.

METHODSA total of 479 subjects with DR,248 with DN and 650 without DR or DN were recruited to assess the associations between SNPs of TCF7L2 (rs7903146, rs6585205, rs11196218), CDKAL1 (rs10946398,rs4712527), SLC30A8 (rs13266634, rs3802177, rs11558471) and HHEX (rs1111875, rs7923837) and the development of DR and DN.

RESULTSThere were significant differences in genotypic and allele frequencies of rs11558471 (SLC30A8) between DR and control groups (P< 0.05), the odds ratio (OR) values of A and AA were 1.27 and 1.68. The distributions of genotype and allele frequency for rs11196218 (TCF7L2) were significantly different between DN and control group (P=0.0051,OR=1.37). However, the P value after Bonferroni correction showed no significant difference. No significant differences were found in the distributions of rs13266634 and rs3802177 (SLC30A8), rs10946398 (CDKAL1), rs6585205, rs7903146 and rs11196218 (TCF7L2) and rs7923837 (HHEX) between DR and control groups, and nor significant differences were found in distributions of rs6585205 (TCF7L2), rs4712527 (CDKAL1), rs13266634, rs3802177 and rs11558471 (SLC30A8), and 7923837 (HHEX) between DN and control groups, though for all comparison the OR values were greater than 1.

CONCLUSIONPolymorphisms of SLC30A8 and TCF7L2 genes may be associated with the development of DR and DN, respectively. Association between the polymorphisms of CKDAL1, TCF7L2 and HHEX genes and DR, and between the polymorphisms of SLC30A8, HHEX and CDKAL1 genes and DN, cannot be excluded.

Cation Transport Proteins ; genetics ; Cyclin-Dependent Kinase 5 ; genetics ; Diabetes Mellitus, Type 2 ; complications ; genetics ; Diabetic Angiopathies ; genetics ; Female ; Homeodomain Proteins ; genetics ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Transcription Factor 7-Like 2 Protein ; genetics ; Transcription Factors ; genetics ; Zinc Transporter 8 ; tRNA Methyltransferases

BACKGROUNDFetal insulin hypothesis was proposed that the association between low birth weight and type 2 diabetes is principally genetically mediated. The aim of this study was to investigate whether common variants in genes CDKAL1, HHEX, ADCY5, SRR, PTPRD that predisposed to type 2 diabetes were also associated with reduced birthweight in Chinese Han population.

METHODSTwelve single nucleotide polymorphisms (rs7756992/rs10946398 in CDKAL1, rs1111875 in HHEX, rs391300 in SRR, rs17584499 in PTPRD, rs1170806/rs9883204/rs4678017/rs9881942/rs7641344/rs6777397/rs6226243 in ADCY5) were genotyped in 1174 unrelated individuals born in Peking Union Medical College Hospital from 1921 to 1954 by TaqMan allelic discrimination assays, of which 645 had normal glucose tolerance, 181 had developed type 2 diabetes and 348 impaired glucose regulation. Associations of these 12 genetic variants with birthweight and glucose metabolism in later life were analyzed.

RESULTSBirthweight was inversely associated with CDKAL1-rs10946398 (β = -41 g [95% confidence interval [CI]: -80, -3], P = 0.034), common variants both associated with increased risk of impaired glucose metabolism and decreased insulin secretion index later in life. After adjusting for sex, gestational weeks, parity and maternal age, the risk allele of CDKAL1-rs7756992 was associated with reduced birthweight (β = -36 g [95% CI: -72, -0.2], P = 0.048). The risk allele in SRR showed a trend toward a reduction of birthweight (P = 0.085).

CONCLUSIONSThis study identified the association between type 2 diabetes risk variants in CDKAL1 and birthweight in Chinese Han individuals, and the carrier of risk allele within SRR had the trend of reduced birthweight. This demonstrates that there is a clear overlap between the genetics of type 2 diabetes and fetal growth, which proposes that lower birth weight and type 2 diabetes may be two phenotypes of one genotype.

Adenylyl Cyclases ; genetics ; Aged ; Alleles ; Asian Continental Ancestry Group ; genetics ; Birth Weight ; genetics ; Cyclin-Dependent Kinase 5 ; genetics ; Diabetes Mellitus, Type 2 ; genetics ; Female ; Genetic Predisposition to Disease ; genetics ; Homeodomain Proteins ; genetics ; Humans ; Infant, Low Birth Weight ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; genetics ; Receptor-Like Protein Tyrosine Phosphatases, Class 2 ; genetics ; Transcription Factors ; genetics ; tRNA Methyltransferases