Disease relevance of RFC1

• No significant differences in the development of other toxicities or in the plasma methotrexate concentrations were observed for the different MTHFR 677C>T or RFC1 80G>A polymorphisms [1].
• More recently the large subunit of RFC, RFC (p140), has been found to interact with the retinoblastoma (Rb) tumor suppressor and the CCAAT/enhancer-binding protein alpha (C/EBP alpha) transcription factor [2].
• In this report, we describe the purification and properties of recombinant human RFC expressed in Sf9 cells from baculovirus expression vectors [3].
• However, it cannot substitute for RFC in promoting simian virus 40 DNA replication in vitro with crude fractions [4].
• In this study, we hypothesised that genetic variants in RFC1 may modulate risk of oesophageal cancer (EC) and gastric cancer (GC) [5].

High impact information on RFC1

• The clamp loader, replication factor C (RFC), can reverse this mark by unloading PCNA from the replicated DNA [6].
• We have recently delineated a novel 38 amino acid transport signal in the hnRNP A1 protein, termed M9, which confers bidirectional transport across the nuclear envelope [7].
• Transformation of RL01 with a vector p35A1, containing the A1-complementary DNA behind the 35S promotor leads to red flowers of the pelargonidin-type [8].
• RL01 served as a recipient for the transfer of the A1 gene of Zea mays encoding dihydroquercetin 4-reductase, which can reduce dihydrokaempferol and thereby provided the intermediate for pelargonidin biosynthesis [8].
• Most importantly, caspase activity results in a selective substrate specificity, since poly(ADP-ribose) polymerase (PARP), lamin B, and Wee1 kinase, but not DNA fragmentation factor (DFF45) or replication factor C (RFC140), are processed [9].

Chemical compound and disease context of RFC1

• This study found modest evidence for a gene-nutrient interaction between offspring RFC1 genotype and periconceptional intake of folic acid on the risk of congenital heart defects [10].
• Genetic variation of apo A1/C3/A4 is associated with hyperlipidaemia and coronary heart disease [11].
• Only CIC cholesterol and the apo B/apo A-1 ratio contributed strongly to the discrimination between patients with coronary atherosclerosis and those without stenoses [12].
• Autologous RFC did not correlate with delayed cutaneous hypersensitivity to 2,4-dinitrochlorobenzene [13].

Biological context of RFC1

• The authors investigated whether high-dose methotrexate-induced toxicity differed according to the presence of methylenetetrahydrofolate reductase (MTHFR) or reduced folate carrier 1 (RFC1) genetic polymorphism [1].
• The parametric LOD scores for the MSX1-CA and D4S1629 were >1.0 and the SIMIBD P values for D6S1029 and RFC1 are suggestive (<0.06), while the SIMIBD P value of 0.01 for TGFA was significant [14].
• A functionally identical RFC complex has been isolated from Saccharomyces cerevisiae and the deduced amino acid sequences among the corresponding human and yeast subunits are homologous [15].
• An interaction between the MTHFR 677TT and RFC1 80GG genotypes was observed whereby persons with this combination had higher serum tHcy [16].
• The data suggest that the conformation of RFC in the primer recognition complex might change on hydrolysis of ATP [17].

Anatomical context of RFC1

• Replication factor C (RFC) is a five-subunit protein complex required for coordinate leading and lagging strand DNA synthesis during S phase and DNA repair in eukaryotic cells [3].
• RFC1- as well as MTX-1-mediated uptake of a marker substrate into suitable human and rat cell lines increased with proton concentration, was sodium-dependent at neutral pH, and inhibited by folate at acidic pH [18].
• In contrast, the effect of PGA1 on folic acid transport was small (approximately 20% inhibition of total influx), consistent with the observation that the major portion of folic acid transport in CHO cells is mediated by a low pH mechanism distinct from RFC1 [19].
• We show that cleavage of RFC140 during Fas-mediated apoptosis in Jurkat cells and lymphocytes results in generation of multiple fragments [20].
• Northern and/or in situ hybridization analysis of the A1 and A2 genes confirmed their restricted expression to the vessel endothelium [21].

Associations of RFC1 with chemical compounds

• This study suggests but does not prove that the RFC1 80G>A polymorphism may contribute to interindividual variability in responses to high-dose methotrexate [1].
• Human RFC is a protein complex consisting of five distinct subunits that migrate through SDS/polyacrylamide gels as protein bands of 140, 40, 38, 37, and 36 kDa [15].
• In this study, the arginine fingers in RFC were mutated to examine the steps in the PCNA loading mechanism that occur after RFC binds ATP [22].
• Mutant RFC complexes containing rfc2-K71R or rfc3-K59R, carrying a conservative lysine --> arginine mutation, had much milder clamp loading defects that could be partially (rfc2-K71R) or completely (rfc3-K59R) suppressed at high ATP concentrations [23].
• The MTHFR 1298A-->C, RFC1 80G-->A, and GCPII 1561C-->T polymorphisms had no individual effects on serum tHcy or folate concentrations [16].

Physical interactions of RFC1

• In this report, we describe the identification of two separate peptide regions of human PCNA spanning amino acids 36-55 and 196-215 that bind RFC by using the surface plasmon resonance technique [24].
• Interestingly, RFC (p140) also interacts with the tumor suppressor p53 [25].

Enzymatic interactions of RFC1

• On the other hand, the C-terminal truncated RFC inhibits the telomerase activity more than the N-terminal-deleted and full-length RFC p140 [26].

Regulatory relationships of RFC1

• When Rad17 was co-expressed with the four small subunits of RFC in insect cells, these proteins formed a complex of 240 kDa that displayed DNA binding, ATPase activity and binding to its predicted target protein, Rad9-1-1 [27].
• Thus, a certain interaction of the N- and C-terminal regions is considered to be required for RFC p140 to suppress telomerase activity [26].
• Deletion of the p140 N-terminal half, including the DNA ligase homology domain, resulted in the formation of an RFC complex with enhanced activity in replication and PCNA loading [28].
• In other systems, the heteropentameric RFC clamp loader complex stimulates loading of DNA polymerase delta to the primer-template [29].

Other interactions of RFC1

• This report finds that the ATP sites of RFC function in distinct steps during loading of PCNA onto DNA [22].
• Furthermore, RFC37, the third subunit of the RFC complex, competes with RIalpha and displaces it from the RFC40-RIalpha complex [30].
• Clamp and clamp loader structures of the human checkpoint protein complexes, Rad9-1-1 and Rad17-RFC [27].
• Introduction of an alanine at position 210 in place of an arginine also reduced the efficiency of PCNA in supporting RFC-dependent polymerase delta-catalyzed elongation of a singly primed DNA template [24].
• The reconstituted human Chl12-RFC complex functions as a second PCNA loader [4].

Analytical, diagnostic and therapeutic context of RFC1

• To test this hypothesis, we evaluated the associations of the G80A polymorphism of RFC1 with EC and GC risk in a case-control study of 216 EC and 633 GC cases and 673 cancer-free controls in a Chinese population [5].
• Direct observation by electron microscopy reveals that RFC has a closed two-finger structure called the U form in the absence of ATP [31].
• However, Southern blot analysis demonstrated no change in gene copy number nor gross rearrangement of RFC1 in the resistant cells [32].
• The labeled blood group antigens (A1, A2, and B) thus produced were analyzed by sodium dodecyl sulfate gel electrophoresis and by isoelectric focusing [33].
• After removal of adherent cells, early rosette-forming cells (early RFC), which were characterized by early (5 min) rosette formation with sheep blood cells (SRBC) at an SRBC to lymphocyte ratio of 8:1, were separated from nonrosetting cells by sedimentation on Ficoll-Hypaque gradient [34].

References