Disease relevance of XRN1

• In the current study, we cloned a human SEP1 gene as a GDNF-inducible gene using human neuroblastoma cells that express RET and GFRalpha1 [1].
• We show loss or reduced expression of hSEP1 messenger RNA (mRNA) in three of four primary osteogenic sarcoma (OGS)-derived cell lines and in eight of nine OGS biopsy specimen [2].
• A mutation in the RNase MRP RNA confers Li+ hypersensitivity and is synthetically lethal with mutations in either HAL2 or XRN1 [3].
• Both SEP1 and SEP2 were predictive of later cerebral palsy (CP) (p = 0.03 and p = 0.003, respectively) [4].
• SEP1 and SEP2 were less accurate than head ultrasound findings of periventricular leukomalacia in the prediction of later CP (73, 69 and 93%, respectively) [4].

High impact information on XRN1

• mRNA decay: x (XRN1) marks the spot [5].
• In this pathway, splice-defective lariat intermediates are debranched by Dbr1p and subsequently degraded 5' to 3' primarily by the cytoplasmic exonuclease, Xrn1p [6].
• In that Xrn1p and Ski2p are cytoplasmic and Dbr1p localizes to both the nucleus and the cytoplasm, these data suggest that this decay pathway occurs within the cytoplasm [6].
• They are also dispersed by inhibitors of translational elongation and share several protein components, including Fas-activated serine/threonine phosphoprotein, XRN1, eIF4E, and tristetraprolin (TTP) [7].
• The induction of the SEP1 gene showed two peaks at 0.5-2 h and 24-48 h after GDNF stimulation by Northern blotting and quantitative real-time reverse transcriptase polymerase chain reaction [1].

Biological context of XRN1

• Taken together, these results suggest that hSEP1 acts as a tumor suppressor gene in OGS [2].
• The hSEP1 gene is located in chromosome 3 at 3q25-26.1 between markers D3S1309 and D3S1569 [2].
• The homozygous mutation in the hSEP1 mRNA in TE85 cell line suggest that this gene itself is subject to LOH [2].
• Importantly, we identified a homozygous missense mutation involving a CG-dinucleotide leading to a change in a conserved amino acid, aspartic acid(1137) >asparagine, in the primary OGS-derived cell line, TE85. hSEP1 mRNA expression was nearly undetectable in TE85 and low in U2OS cell lines [2].
• Yeast SEP1 is a multifunctional gene that regulates a variety of nuclear and cytoplasmic functions including homologous recombination, meiosis, telomere maintenance, RNA metabolism and microtubule assembly [2].

Anatomical context of XRN1

• Identification of human SEP1 as a glial cell line-derived neurotrophic factor-inducible protein and its expression in the nervous system [1].
• In addition, we found a high level of SEP1 expression in neurons of the dorsal root and superior cervical ganglia and motor neurons of the spinal cord of mice in which RET is also expressed [1].
• Immunostaining revealed that the expression of the SEP1 protein was detected in cell body, elongated neurites and growth cone-like structure of neuroblastoma cells treated with GDNF [1].
• Northern blot analysis showed a major 10-kb mRNA expressed ubiquitously in various organs as well as a minor 5.5-kb mRNA expressed relatively highly in the testis and placenta. hSEP1p is localized in the cytoplasm as examined by cytochemical and Western blot analyses of fractionated cellular extracts [8].
• We recorded unilateral, median nerve SEPs in 88 preterm infants twice in the first 3 weeks of life (SEP1 and SEP2) [4].

Analytical, diagnostic and therapeutic context of XRN1

• The late induction was also confirmed at protein levels by Western blotting with anti-SEP1 antibody [1].

References