Organization and Conservation of the GART/SON/DONSON Locus in Mouse and Human Genomes

Wynn, Sarah; Fisher, Rosemary A.; Pagel, Charles N.; Price, Michael; Liu, Qiu Yan; Khan, Ilyas; Zammit, Peter S.; Dadrah, Kulwinder; Mazrani, Waseem; Kessling, Anna M.; Lee, Janet; Buluwela, Lakjaya

doi:10.1006/geno.2000.6254

Cited by 32 publications

(54 citation statements)

References 24 publications

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“…GART gene is located in chromosome 21q22.11. The protein encoded by this gene is a trifunctional polypeptide, which has phosphoribosylglycinamide formyltransferase, phosphoribosylglycinamide synthetase, and phosphoribosylaminoimidazole synthetase activity which is required for de novo purine biosynthesis [34][35][36]. All of our findings validated the importance of OCM genes in carcinogenesis of liver cell.…”

Section: Discussionsupporting

confidence: 82%

Genetic variations in the one-carbon metabolism pathway genes and susceptibility to hepatocellular carcinoma risk: a case–control study

Zhang

Liu²,

Han³

et al. 2014

Tumor Biol.

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Hepatocellular carcinoma (HCC) is the sixth common cancer and the third common cause of cancer mortality worldwide. However, the exact molecular mechanism of HCC remains uncertain. Many enzymes are involved in one-carbon metabolism (OCM), and single nucleotide polymorphisms (SNPs) in the corresponding genes may play a role in liver carcinogenesis. In this study, we enrolled 1500 HCC patients and 1500 cancer-free controls, which were frequency-matched by age, gender, and HBV infection status. Then eight SNPs from seven OCM genes (MTHFR, MTR, MTRR, FTHFD, GART, SHMT, and CBS) were evaluated. Results showed that six SNPs (MTHFR rs1801133, MTRR rs2287780, MTRR rs10380, FTHFD rs1127717, GART rs8971, and SHMT rs1979277) were significantly associated with HCC risk in Chinese population, with P values range from 2.26 × 10(-4) to 0.035). The most significant association was detected for GART rs8971. Compared with individuals with the TT genotype, the age- and sex-adjusted odds ratio (OR) for developing HCC was 1.44 (95% confidence interval (CI): 1.03-2.02) among those with the CC genotype and 1.30 (95% CI: 1.10-1.53) for those with CT genotype. Under the log-additive model, each additional copy of minor allele C was associated with a 1.28-fold increased risk of HCC (OR = 1.28, 95% CI: 1.12-1.45). These findings indicated that genetic variants in OCM genes might contribute to HCC susceptibility.

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Section: Discussionsupporting

confidence: 82%

Genetic variations in the one-carbon metabolism pathway genes and susceptibility to hepatocellular carcinoma risk: a case–control study

Zhang

Liu²,

Han³

et al. 2014

Tumor Biol.

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“…4A and B). An interaction with the DNA binding protein SON, which contains a stretch of RS dipeptides similar to the ones identified in SR proteins (68), was also detected. We confirmed these twohybrid interactions by testing that SRrp53 used as a bait directly interacted with HCC1 and that Luc7p and SON fused to an activation domain (Fig.…”

Section: Resultsmentioning

confidence: 67%

A Novel SR-Related Protein Is Required for the Second Step of Pre-mRNA Splicing

Cazalla

Newton

Cáceres

2005

Molecular and Cellular Biology

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The SR family proteins and SR-related polypeptides are important regulators of pre-mRNA splicing. A novel SR-related protein of an apparent molecular mass of 53 kDa was isolated in a gene trap screen that identifies proteins which localize to the nuclear speckles. This novel protein possesses an arginine-and serine-rich domain and was termed SRrp53 (for SR-related protein of 53 kDa). In support for a role of this novel RS-containing protein in pre-mRNA splicing, we identified the mouse ortholog of the Saccharomyces cerevisiae U1 snRNP-specific protein Luc7p and the U2AF 65 -related factor HCC1 as interacting proteins. In addition, SRrp53 is able to interact with some members of the SR family of proteins and with U2AF 35 in a yeast two-hybrid system and in cell extracts. We show that in HeLa nuclear extracts immunodepleted of SRrp53, the second step of pre-mRNA splicing is blocked, and recombinant SRrp53 is able to restore splicing activity. SRrp53 also regulates alternative splicing in a concentration-dependent manner. Taken together, these results suggest that SRrp53 is a novel SR-related protein that has a role both in constitutive and in alternative splicing.Pre-mRNA splicing takes place in the spliceosome, a large ribonucleoprotein complex that is formed by the small nuclear ribonucleoprotein particles (U1, U2, U4/U6, and U5 snRNPs) and numerous non-snRNP splicing factors (reviewed in reference 36).The serine-and arginine-rich proteins (SR proteins) are a highly conserved family of structurally and functionally related non-snRNP splicing factors with a dual role in splicing, affecting both constitutive and alternative splicing. They have a modular domain structure consisting of one or two RNA recognition motifs (RRMs) and a C-terminal domain rich in arginine and serine residues, termed the RS domain (20). The RRMs determine RNA binding specificity, whereas the RS domain, which is extensively phosphorylated, promotes protein-protein interactions that are essential for the recruitment of the splicing apparatus and for splice site pairing (61, 67). The RS domains have been shown to directly contact the pre-mRNA branch point; thus, RS domains may not solely function through protein-protein interactions (53). In addition, the RS domain of SR proteins directs subcellular localization and determines the nucleocytoplasmic shuttling of individual SR proteins (10,27,39).The SR family proteins function early in spliceosome formation and are involved in multiple steps of the splicing reaction (59). They facilitate the recruitment of the U1 snRNP particle to the 5Ј splice site (18,33,35) and also bridge the 5Ј and 3Ј splice sites via RS-domain-mediated interactions with U1 and U2 snRNP-associated proteins (67). The SR family proteins also participate at later stages of the splicing reaction, when they facilitate the recruitment of the U4/U6 ⅐ U5 trisnRNP complex (48).A class of related RS-domain-containing proteins that may or may not contain RRMs is also involved in splicing regulation and has been termed the SR-protein...

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“…Similar forms of full-length and the short splice variants (Son f, Son b and Son e) have been predicted in mice (for details, see Figures 5A, S5A and Table S1). Interestingly, exon 5a is extremely well conserved between human and mouse (Wynn et al, 2000), suggesting functional significance of the isoforms made by inclusion of this alternative exon. Despite such information, no experimental data have proven the expression of these SON splice variants.…”

Section: Resultsmentioning

confidence: 99%

SON and Its Alternatively Spliced Isoforms Control MLL Complex-Mediated H3K4me3 and Transcription of Leukemia-Associated Genes

et al. 2016

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SUMMARY Dysregulation of MLL complex-mediated histone methylation plays a pivotal role in gene expression associated with diseases, but little is known about cellular factors modulating MLL complex activity. Here, we report that SON, previously known as an RNA splicing factor, controls MLL complex-mediated transcriptional initiation. SON binds to DNA near transcription start sites, interacts with menin, and inhibits MLL complex assembly, resulting in decreased H3K4me3 and transcriptional repression. Importantly, alternatively spliced short isoforms of SON are markedly upregulated in acute myeloid leukemia. The short isoforms compete with full-length SON for chromatin occupancy, but lack the menin-binding ability, thereby antagonizing full-length SON function in transcriptional repression while not impairing full-length SON-mediated RNA splicing. Furthermore, overexpression of a short isoform of SON enhances replating potential of hematopoietic progenitors. Our findings define SON as a fine-tuner of the MLL-menin interaction and reveal short SON overexpression as a marker indicating aberrant transcriptional initiation in leukemia.

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Organization and Conservation of the GART/SON/DONSON Locus in Mouse and Human Genomes

Cited by 32 publications

References 24 publications

Genetic variations in the one-carbon metabolism pathway genes and susceptibility to hepatocellular carcinoma risk: a case–control study

Genetic variations in the one-carbon metabolism pathway genes and susceptibility to hepatocellular carcinoma risk: a case–control study

A Novel SR-Related Protein Is Required for the Second Step of Pre-mRNA Splicing

SON and Its Alternatively Spliced Isoforms Control MLL Complex-Mediated H3K4me3 and Transcription of Leukemia-Associated Genes

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