Disease relevance of ELAC1

• Characterization of TRZ1, a yeast homolog of the human candidate prostate cancer susceptibility gene ELAC2 encoding tRNase Z [1].
• Crystal structure of the tRNA 3' processing endoribonuclease tRNase Z from Thermotoga maritima [2].
• These changes could affect tRNase Z processing of mutant pre-tRNAs, perhaps contributing to mitochondrial disease [3].
• V29 did not produce hypotension in the rat system, but D29 did [4].
• Infection of slowly growing mycobacteria with phage (phage D29) was followed by chemical virucide destruction of extracellular phage [5].

High impact information on ELAC1

• Furthermore, only the two previously reported missense changes (Ser217Leu and Ala541Thr) were identified by mutational analysis of all HPC2/ELAC exons in 93 probands with HPC [6].
• Partial purification and separation of RNase Z from the 5' processing activity RNase P allowed us to determine biochemical characteristics of the enzyme [7].
• The precursor for tRNAPhe requires RNA editing for efficient processing by RNase Z [7].
• The 15 patients with T-cell disease had higher D29 MRD than those with B-lineage ALL (P =.01) [8].
• The group of patients with a D29 MRD less than 0.01% included patients with T-cell disease, white blood cell count more than 50 x 10(9)/L at diagnosis, or age 10 years or older, and could not be identified by up-front criteria [8].

Biological context of ELAC1

• In the human genome exists a gene, ELAC1, which seems to correspond to the C-terminal half of 3' tRNase from ELAC2 [9].
• Naturally occurring mutations in human mitochondrial pre-tRNASer(UCN) can affect the transfer ribonuclease Z cleavage site, processing kinetics, and substrate secondary structure [3].
• Comparison with its nuclear and mitochondrial homologs revealed that the substrate specificity of the archaeal RNase Z is narrower than that of the nuclear RNase Z but broader than that of the mitochondrial RNase Z [10].
• Mitochondrial pretRNA(His) is processed by the nuclear RNase Z, generating a mature tRNA(His) containing an 8 base pair acceptor stem [11].
• To our surprise, the newly isolated proteins T. maritima and T. thermophilus showed the weak tRNase Z activity, even though their primary amino acid sequences are, on the whole, quite different from those of the typical tRNase Zs [12].

Anatomical context of ELAC1

• This enzyme has been characterized from representatives of all three domains of life (Bacteria, Archaea and Eukarya), as well as from mitochondria and chloroplasts. tRNase Z enzymes come in two forms: short versions (280-360 amino acids in length), present in all three kingdoms, and long versions (750-930 amino acids), present only in eukaryotes [13].
• In vitro assays using partially purified HeLa cell RNase P and mitochondrial tRNA 3' processing endonuclease (tRNase Z) confirmed that the efficiency of both 5' and 3' processing was impaired [14].
• Between May 1993 and August 1994, 27 patients with loco-regional squamous cell carcinoma of the esophagus were treated with 2 courses of combined fluorouracil(1000mg per square meter of body-surface area daily for 5 days) and cisplatin(60mg per square meter on the first day)(D1 and D29) plus 48Gy of radiation therapy(RT) over 4 weeks [15].

Associations of ELAC1 with chemical compounds

• Trz1p has two putative nucleotide triphosphate-binding motifs (P-loop) and a conserved histidine motif [1].
• The histidine motif and the putative nucleotide binding motif at the C-domain are important for Trz1p function because mutant proteins bearing changes to the critical residues in these motifs are unable to rescue deletion of TRZ1 [1].
• Our X-ray data (resolution ranging from 2.2 to 1.2 A) reveal strong interactions between the bis-tetrahydrofuranyl urethane moiety of TMC114 and main-chain atoms of D29 and D30 [16].
• RNase Z leaves 5' terminal phosphoryl and 3' terminal hydroxyl groups at the processing products [11].
• The therapeutic indices, which mark the extent of the therapeutically effective dose, of V29 (29Arg-->Val) and D29 (-->Asp) were 3.5 and 3.2, respectively, whereas that of rhTNF was 1 [4].

Analytical, diagnostic and therapeutic context of ELAC1

• Further trials are needed to reveal whether such patients with D29 MRD less than 0.01% can be cured with less intensive chemotherapy, which would reduce the risk of serious late effects as well as the costs of therapy [8].
• No patients with a MRD level less than 0.01% on D29 have so far had a relapse, whereas the 7-year probability of event-free survival for patients with higher MRD levels was 0.52 (P =.0007) [8].

References