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TREX1  -  three prime repair exonuclease 1

Homo sapiens

Synonyms: 3'-5' exonuclease TREX1, AGS1, CRV, DNase III, DRN3, ...
 
 
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Disease relevance of TREX1

  • Expression of TREX1 and TREX2 in Escherichia coli demonstrates that these recombinant proteins are active 3'-->5' exonucleases [1].
  • The HSV-1 immediate early protein ICP0 is sufficient to induce the redistribution of ATRIP [2].
  • These results not only identify hTREX84 as a prognosticator of breast cancer but also delineate human TREX complex as a target for therapeutic drugs against breast cancer [3].
  • Therapeutic red cell-exchange (TREX) has been used with much interest over the years, starting with the management of hemolytic disease of the newborn and later used to correct severe anemia in thalassemia patients thereby preventing iron overload [4].
  • We report a heterozygous TREX1 mutation causing familial chilblain lupus [5].
  • By comparison, the TREX1 R114H homozygous mutation causes AGS and is found as a heterozygous mutation in systemic lupus erythematosus [6].
 

High impact information on TREX1

  • Deletion of ATR mediated by the Cre recombinase caused the loss of ATR and ATRIP expression, loss of DNA damage checkpoint responses, and cell death [7].
  • Thus, ATRIP and ATR are mutually dependent partners in cell cycle checkpoint signaling pathways [7].
  • After granzyme A activates NM23-H1 to make single-stranded nicks, TREX1 removes nucleotides from the nicked 3' end to reduce the possibility of repair by rejoining the nicked ends [8].
  • Silencing NM23-H1 or TREX1 inhibits DNA damage and death of cells treated with perforin (PFN) and granzyme A, but not of cells treated with perforin and granzyme B (GzmB) [8].
  • These results suggest that MMR proteins can act as direct sensors of methylation damage and help recruit ATR-ATRIP to sites of cytotoxic O(6)-meG adducts to initiate ATR checkpoint signaling [9].
 

Biological context of TREX1

  • These novel cDNAs and sequences in the GenBank data base indicate that transcripts containing the TREX1 and TREX2 ORFs are produced using a variety of mechanisms that include alternate promoter usage, alternative splicing, and varied sites for 3' cleavage and polyadenylation [10].
  • The 5'-flanking sequences indicate transcription initiation from consensus putative promoters identified -140 and -650 base pairs upstream of the TREX1 open reading frame (ORF) and -623 and -753 base pairs upstream of the TREX2 ORF [10].
  • Identification of the TREX1 and TREX2 cDNA sequences provides the genetic tools to investigate the physiological roles of these exonucleases in mammalian DNA replication, repair, and recombination pathways [1].
  • Analysis of the TREX1 and TREX2 sequences identifies three conserved motifs that likely generate the exonuclease active site in these enzymes [1].
  • Replacing the ATRIP coiled-coil domain with a heterologous dimerization domain restored stable binding to ATR and localization to damage-induced intranuclear foci [11].
 

Anatomical context of TREX1

  • The RNA binding and export factor (REF) family of mRNA export adaptors are found in several nuclear protein complexes including the spliceosome, TREX, and exon junction complexes [12].
 

Associations of TREX1 with chemical compounds

  • ATM and rad3-related protein kinase (ATR), a member of the phosphoinositide kinase-like protein kinase family, plays a critical role in cellular responses to DNA structural abnormalities in conjunction with its interacting protein, ATRIP [13].
  • However, all 3'-phosphoglycolate substrates, as well as a 3'-phosphate substrate, were resistant to DNase III under conditions in which the analogous 3'-hydroxyl substrates were extensively degraded [14].
  • We detected the presence of a conserved proline-rich region on the surface of TREX1 [15].
  • The structure also reveals an 8-amino acid polyproline II helix within the TREX1 enzyme that suggests a mechanism for interactions of this exonuclease with other protein complexes [16].
 

Physical interactions of TREX1

 

Other interactions of TREX1

 

Analytical, diagnostic and therapeutic context of TREX1

  • MATERIALS AND METHODS: A total of 201 cases consisting of nonprocessed soft copy versions of the digital mammograms acquired from GE, Fischer, and Trex digital mammography systems (1997-1999) and conventional screen-film mammograms of the same patients were interpreted by nine radiologists [21].

References

  1. Identification and expression of the TREX1 and TREX2 cDNA sequences encoding mammalian 3'-->5' exonucleases. Mazur, D.J., Perrino, F.W. J. Biol. Chem. (1999) [Pubmed]
  2. Herpes simplex virus type I disrupts the ATR-dependent DNA-damage response during lytic infection. Wilkinson, D.E., Weller, S.K. J. Cell. Sci. (2006) [Pubmed]
  3. Linking transcriptional elongation and messenger RNA export to metastatic breast cancers. Guo, S., Hakimi, M.A., Baillat, D., Chen, X., Farber, M.J., Klein-Szanto, A.J., Cooch, N.S., Godwin, A.K., Shiekhattar, R. Cancer Res. (2005) [Pubmed]
  4. Clinical application of therapeutic erythrocytapheresis (TEA). Valbonesi, M., Bruni, R. Transfusion science. (2000) [Pubmed]
  5. Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome. Rice, G., Newman, W.G., Dean, J., Patrick, T., Parmar, R., Flintoff, K., Robins, P., Harvey, S., Hollis, T., O'Hara, A., Herrick, A.L., Bowden, A.P., Perrino, F.W., Lindahl, T., Barnes, D.E., Crow, Y.J. Am. J. Hum. Genet. (2007) [Pubmed]
  6. The TREX1 double-stranded DNA degradation activity is defective in dominant mutations associated with autoimmune disease. Lehtinen, D.A., Harvey, S., Mulcahy, M.J., Hollis, T., Perrino, F.W. J. Biol. Chem. (2008) [Pubmed]
  7. ATR and ATRIP: partners in checkpoint signaling. Cortez, D., Guntuku, S., Qin, J., Elledge, S.J. Science (2001) [Pubmed]
  8. The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death. Chowdhury, D., Beresford, P.J., Zhu, P., Zhang, D., Sung, J.S., Demple, B., Perrino, F.W., Lieberman, J. Mol. Cell (2006) [Pubmed]
  9. ATR kinase activation mediated by MutSalpha and MutLalpha in response to cytotoxic O6-methylguanine adducts. Yoshioka, K., Yoshioka, Y., Hsieh, P. Mol. Cell (2006) [Pubmed]
  10. Structure and expression of the TREX1 and TREX2 3' --> 5' exonuclease genes. Mazur, D.J., Perrino, F.W. J. Biol. Chem. (2001) [Pubmed]
  11. ATRIP oligomerization is required for ATR-dependent checkpoint signaling. Ball, H.L., Cortez, D. J. Biol. Chem. (2005) [Pubmed]
  12. The solution structure of REF2-I reveals interdomain interactions and regions involved in binding mRNA export factors and RNA. Golovanov, A.P., Hautbergue, G.M., Tintaru, A.M., Lian, L.Y., Wilson, S.A. RNA (2006) [Pubmed]
  13. Amino-terminal domain of ATRIP contributes to intranuclear relocation of the ATR-ATRIP complex following DNA damage. Itakura, E., Takai, K.K., Umeda, K., Kimura, M., Ohsumi, M., Tamai, K., Matsuura, A. FEBS Lett. (2004) [Pubmed]
  14. Resistance of 3'-phosphoglycolate DNA ends to digestion by mammalian DNase III. Inamdar, K.V., Yu, Y., Povirk, L.F. Radiat. Res. (2002) [Pubmed]
  15. Structure of the dimeric exonuclease TREX1 in complex with DNA displays a proline-rich binding site for WW Domains. Brucet, M., Querol-Audí, J., Serra, M., Ramirez-Espain, X., Bertlik, K., Ruiz, L., Lloberas, J., Macias, M.J., Fita, I., Celada, A. J. Biol. Chem. (2007) [Pubmed]
  16. The crystal structure of TREX1 explains the 3' nucleotide specificity and reveals a polyproline II helix for protein partnering. de Silva, U., Choudhury, S., Bailey, S.L., Harvey, S., Perrino, F.W., Hollis, T. J. Biol. Chem. (2007) [Pubmed]
  17. Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases. Cortez, D., Glick, G., Elledge, S.J. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  18. A novel protein activity mediates DNA binding of an ATR-ATRIP complex. Bomgarden, R.D., Yean, D., Yee, M.C., Cimprich, K.A. J. Biol. Chem. (2004) [Pubmed]
  19. Quaternary structure of ATR and effects of ATRIP and replication protein A on its DNA binding and kinase activities. Unsal-Kaçmaz, K., Sancar, A. Mol. Cell. Biol. (2004) [Pubmed]
  20. Recruitment of ATR-ATRIP, Rad17, and 9-1-1 complexes to DNA damage. Yang, X.H., Zou, L. Meth. Enzymol. (2006) [Pubmed]
  21. The effects of gray scale image processing on digital mammography interpretation performance. Cole, E.B., Pisano, E.D., Zeng, D., Muller, K., Aylward, S.R., Park, S., Kuzmiak, C., Koomen, M., Pavic, D., Walsh, R., Baker, J., Gimenez, E.I., Freimanis, R. Academic radiology. (2005) [Pubmed]
 
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