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• W2014207515 abstract "TREX1 is a 3′-deoxyribonuclease that degrades single- and double-stranded DNA (ssDNA and dsDNA) to prevent inappropriate nucleic acid-mediated immune activation. More than 40 different disease-causing TREX1 mutations have been identified exhibiting dominant and recessive genetic phenotypes in a spectrum of autoimmune disorders. Mutations in TREX1 at positions Asp-18 and Asp-200 to His and Asn exhibit dominant autoimmune phenotypes associated with the clinical disorders familial chilblain lupus and Aicardi-Goutières syndrome. Our previous biochemical studies showed that the TREX1 dominant autoimmune disease phenotype depends upon an intact DNA-binding process coupled with dysfunctional active site chemistry. Studies here show that the TREX1 Arg-62 residues extend across the dimer interface into the active site of the opposing protomer to coordinate substrate DNA and to affect catalysis in the opposing protomer. The TREX1R62A/R62A homodimer exhibits ∼50-fold reduced ssDNA and dsDNA degradation activities relative to TREX1WT. The TREX1 D18H, D18N, D200H, and D200N dominant mutant enzymes were prepared as compound heterodimers with the TREX1 R62A substitution in the opposing protomer. The TREX1D18H/R62A, TREX1D18N/R62A, TREX1D200H/R62A, and TREX1D200N/R62A compound heterodimers exhibit higher levels of ss- and dsDNA degradation activities than the homodimers demonstrating the requirement for TREX1 Arg-62 residues to provide necessary structural elements for full catalytic activity in the opposing TREX1 protomer. This concept is further supported by the loss of dominant negative effects in the TREX1 D18H, D18N, D200H, and D200N compound heterodimers. These data provide compelling evidence for the required TREX1 dimeric structure for full catalytic function.Background: The structure of TREX1 exonuclease identifies key residues positioned at the stable dimer interface.Results: The TREX1 Arg-62 acts across the dimer interface to affect DNA binding and catalysis in the opposing protomer.Conclusion: TREX1 is a functional dimer.Significance: These data help us understand how heterozygous TREX1 mutations can contribute to disease. TREX1 is a 3′-deoxyribonuclease that degrades single- and double-stranded DNA (ssDNA and dsDNA) to prevent inappropriate nucleic acid-mediated immune activation. More than 40 different disease-causing TREX1 mutations have been identified exhibiting dominant and recessive genetic phenotypes in a spectrum of autoimmune disorders. Mutations in TREX1 at positions Asp-18 and Asp-200 to His and Asn exhibit dominant autoimmune phenotypes associated with the clinical disorders familial chilblain lupus and Aicardi-Goutières syndrome. Our previous biochemical studies showed that the TREX1 dominant autoimmune disease phenotype depends upon an intact DNA-binding process coupled with dysfunctional active site chemistry. Studies here show that the TREX1 Arg-62 residues extend across the dimer interface into the active site of the opposing protomer to coordinate substrate DNA and to affect catalysis in the opposing protomer. The TREX1R62A/R62A homodimer exhibits ∼50-fold reduced ssDNA and dsDNA degradation activities relative to TREX1WT. The TREX1 D18H, D18N, D200H, and D200N dominant mutant enzymes were prepared as compound heterodimers with the TREX1 R62A substitution in the opposing protomer. The TREX1D18H/R62A, TREX1D18N/R62A, TREX1D200H/R62A, and TREX1D200N/R62A compound heterodimers exhibit higher levels of ss- and dsDNA degradation activities than the homodimers demonstrating the requirement for TREX1 Arg-62 residues to provide necessary structural elements for full catalytic activity in the opposing TREX1 protomer. This concept is further supported by the loss of dominant negative effects in the TREX1 D18H, D18N, D200H, and D200N compound heterodimers. These data provide compelling evidence for the required TREX1 dimeric structure for full catalytic function. Background: The structure of TREX1 exonuclease identifies key residues positioned at the stable dimer interface. Results: The TREX1 Arg-62 acts across the dimer interface to affect DNA binding and catalysis in the opposing protomer. Conclusion: TREX1 is a functional dimer. Significance: These data help us understand how heterozygous TREX1 mutations can contribute to disease. The TREX1 gene has a simple single open reading frame structure that maps to chromosome 3p21.31 and encodes the most active 3′→5′-exonuclease in multiple mammalian tissues (1.Lindahl T. Gally J.A. Edelman G.M. et al.Properties of deoxyribonuclease III from mammalian tissues.J. Biol. Chem. 1969; 244: 5014-5019Abstract Full Text PDF PubMed Google Scholar2.Perrino F.W. Miller H. Ealey K.A. et al.Identification of a 3′→5′-exonuclease that removes cytosine arabinoside monophosphate from 3′ termini of DNA.J. Biol. Chem. 1994; 269: 16357-16363Abstract Full Text PDF PubMed Google Scholar, 3.Perrino F.W. Mazur D.J. Ward H. Harvey S. et al.Exonucleases and the incorporation of aranucleotides into DNA.Cell Biochem. Biophys. 1999; 30: 331-352Crossref PubMed Google Scholar, 4.Höss M. Robins P. Naven T.J. Pappin D.J. Sgouros J. Lindahl T. et al.A human DNA editing enzyme homologous to the Escherichia coli DnaQ/MutD protein.EMBO J. 1999; 18: 3868-3875Crossref PubMed Scopus (148) Google Scholar, 5.Mazur D.J. Perrino F.W. et al.Identification and expression of the TREX1 and TREX2 cDNA sequences encoding mammalian 3′→5′ exonucleases.J. Biol. Chem. 1999; 274: 19655-19660Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 6.Mazur D.J. Perrino F.W. et al.Structure and expression of the TREX1 and TREX2 3′ → 5′ exonuclease genes.J. Biol. Chem. 2001; 276: 14718-14727Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar7.Mazur D.J. Perrino F.W. et al.Excision of 3′ termini by the Trex1 and TREX2 3′→5′ exonucleases. Characterization of the recombinant proteins.J. Biol. Chem. 2001; 276: 17022-17029Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). Mutations in the TREX1 gene have now been identified to cause a spectrum of autoimmune disorders, including Aicardi-Goutières syndrome (AGS), 2The abbreviations used are: AGSAicardi-Goutières syndromeFCLfamilial chilblain lupusssDNAsingle-stranded DNAdNMPdeoxynucleoside monophosphateFAMfluorescent fluorescein. Cree encephalitis, familial chilblain lupus (FCL), retinal vasculopathy with cerebral leukodystrophy, and are associated with systemic lupus erythematosus (8.Crow Y.J. Hayward B.E. Parmar R. Robins P. Leitch A. Ali M. Black D.N. van Bokhoven H. Brunner H.G. Hamel B.C. Corry P.C. Cowan F.M. Frints S.G. Klepper J. Livingston J.H. Lynch S.A. Massey R.F. Meritet J.F. Michaud J.L. Ponsot G. Voit T. Lebon P. Bonthron D.T. Jackson A.P. Barnes D.E. Lindahl T. et al.Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus.Nat. Genet. 2006; 38: 917-920Crossref PubMed Scopus (657) Google Scholar9.Black D.N. Watters G.V. Andermann E. Dumont C. Kabay M.E. Kaplan P. Meagher-Villemure K. Michaud J. O'Gorman G. Reece E. et al.Encephalitis among Cree children in northern Quebec.Ann. Neurol. 1988; 24: 483-489Crossref PubMed Scopus (48) Google Scholar, 10.Crow Y.J. Black D.N. Ali M. Bond J. Jackson A.P. Lefson M. Michaud J. Roberts E. Stephenson J.B. Woods C.G. Lebon P. et al.Cree encephalitis is allelic with Aicardi-Goutieres syndrome: implications for the pathogenesis of disorders of interferon α metabolism.J. Med. Genet. 2003; 40: 183-187Crossref PubMed Scopus (94) Google Scholar, 11.Stephenson J.B. et al.Aicardi-Goutieres syndrome (AGS).Eur. J. Paediatr. Neurol. 2008; 12: 355-358Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 12.Lee-Kirsch M.A. Gong M. Schulz H. Rüschendorf F. Stein A. Pfeiffer C. Ballarini A. Gahr M. Hubner N. Linné M. et al.Familial chilblain lupus, a monogenic form of cutaneous lupus erythematosus, maps to chromosome 3p.Am. J. Hum. Genet. 2006; 79: 731-737Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 13.Lee-Kirsch M.A. Chowdhury D. Harvey S. Gong M. Senenko L. Engel K. Pfeiffer C. Hollis T. Gahr M. Perrino F.W. Lieberman J. Hubner N. et al.A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus.J. Mol. Med. 2007; 85: 531-537Crossref PubMed Scopus (171) Google Scholar, 14.Rice G. Patrick T. Parmar R. Taylor C.F. Aeby A. Aicardi J. Artuch R. et al.Clinical and molecular phenotype of aicardi-goutieres syndrome.Am. J. Hum. Genet. 2007; 81: 713-725Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar, 15.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. et al.Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome.Am. J. Hum. Genet. 2007; 80: 811-815Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar, 16.Hedrich C.M. Fiebig B. Hauck F.H. Sallmann S. Hahn G. Pfeiffer C. Heubner G. Lee-Kirsch M.A. Gahr M. et al.Chilblain lupus erythematosus-a review of literature.Clin. Rheumatol. 2008; 27: 1341Crossref PubMed Scopus (14) Google Scholar, 17.Crow Y.J. Rehwinkel J. et al.Aicardi-Goutieres syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity.Hum. Mol. Genet. 2009; 18: R130-136Crossref PubMed Scopus (237) Google Scholar, 18.Günther C. Meurer M. Stein A. Viehweg A. Lee-Kirsch M.A. et al.Familial chilblain lupus–a monogenic form of cutaneous lupus erythematosus due to a heterozygous mutation in TREX1.Dermatology. 2009; 219: 162-166Crossref PubMed Scopus (44) Google Scholar, 19.Prendiville J.S. Crow Y.J. et al.Blue (or purple) toes: chilblains or chilblain lupus-like lesions are a manifestation of Aicardi-Goutieres syndrome and familial chilblain lupus.J. Am. Acad. Dermatol. 2009; 61: 727-728Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 20.Richards A. van den Maagdenberg A.M. Jen J.C. Kavanagh D. Bertram P. Spitzer D. Liszewski M.K. Barilla-Labarca M.L. Terwindt G.M. Kasai Y. McLellan M. Grand M.G. Vanmolkot K.R. de Vries B. Wan J. Kane M.J. Mamsa H. Schäfer R. Stam A.H. Haan J. de Jong P.T. Storimans C.W. van Schooneveld M.J. Oosterhuis J.A. Gschwendter A. Dichgans M. Kotschet K.E. Hodgkinson S. Hardy T.A. Delatycki M.B. Hajj-Ali R.A. Kothari P.H. Nelson S.F. Frants R.R. Baloh R.W. Ferrari M.D. Atkinson J.P. et al.C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy.Nat. Genet. 2007; 39: 1068-1070Crossref PubMed Scopus (317) Google Scholar, 21.Stam A.H. Haan J. van den Maagdenberg A.M. Ferrari M.D. Terwindt G.M. et al.Migraine and genetic and acquired vasculopathies.Cephalalgia. 2009; 29: 1006-1017Crossref PubMed Scopus (49) Google Scholar, 22.Gruver A.M. Schoenfield L. Coleman J.F. Hajj-Ali R. Rodriguez E.R. Tan C.D. et al.Novel ophthalmic pathology in an autopsy case of autosomal dominant retinal vasculopathy with cerebral leukodystrophy.J. Neuroophthalmol. 2011; 31: 20-24Crossref PubMed Scopus (7) Google Scholar, 23.Lee-Kirsch M.A. Gong M. Chowdhury D. Senenko L. Engel K. Lee Y.A. de Silva U. Bailey S.L. Witte T. Vyse T.J. Kere J. Pfeiffer C. Harvey S. Wong A. Koskenmies S. Hummel O. Rohde K. Schmidt R.E. Dominiczak A.F. Gahr M. Hollis T. Perrino F.W. Lieberman J. Hübner N. et al.Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus.Nat. Genet. 2007; 39: 1065-1067Crossref PubMed Scopus (522) Google Scholar, 24.de Vries B. Steup-Beekman G.M. Haan J. Bollen E.L. Luyendijk J. Frants R.R. Terwindt G.M. van Buchem M.A. Huizinga T.W. van den Maagdenberg A.M. Ferrari M.D. et al.TREX1 gene variant in neuropsychiatric systemic lupus erythematosus.Ann. Rheum. Dis. 2010; 69: 1886-1887Crossref PubMed Scopus (42) Google Scholar25.Namjou B. Kothari P.H. Kelly J.A. Glenn S.B. Ojwang J.O. Adler A. Alarcón-Riquelme M.E. Gallant C.J. Boackle S.A. Criswell L.A. Kimberly R.P. Brown E. Edberg J. Stevens A.M. Jacob C.O. Tsao B.P. Gilkeson G.S. Kamen D.L. Merrill J.T. Petri M. Goldman R.R. Vila L.M. Anaya J.M. Niewold T.B. Martin J. Pons-Estel B.A. Sabio J.M. Callejas J.L. Vyse T.J. Bae S.C. Perrino F.W. Freedman B.I. Scofield R.H. Moser K.L. Gaffney P.M. James J.A. Langefeld C.D. Kaufman K.M. Harley J.B. Atkinson J.P. et al.Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort.Genes Immun. 2011; 12: 270-279Crossref PubMed Scopus (207) Google Scholar). Genetic discoveries from these autoimmune disease patients have now identified more than 40 different TREX1 disease-causing and -associated mutations that exhibit dominant and recessive genetics and occur as inherited or de novo mutations, dependent upon the specific mutant allele. The TREX1 disease alleles include missense mutations, insertions, duplications, and frame shifts that locate to positions throughout the 314-amino acid-coding gene. These findings have established a causal relationship between TREX1 genetic variants and multiple mechanisms of TREX1 enzyme dysfunction that might explain the spectrum of human autoimmune disorders with overlapping clinical symptoms related to TREX1 DNA degradation and immune activation. Aicardi-Goutières syndrome familial chilblain lupus single-stranded DNA deoxynucleoside monophosphate fluorescent fluorescein. The TREX1 enzyme contains an N-terminal 242 amino acids with all of the necessary structural elements for full catalytic activity and a C-terminal region of 72 amino acids required for cytosolic localization to the perinuclear space (20.Richards A. van den Maagdenberg A.M. Jen J.C. Kavanagh D. Bertram P. Spitzer D. Liszewski M.K. Barilla-Labarca M.L. Terwindt G.M. Kasai Y. McLellan M. Grand M.G. Vanmolkot K.R. de Vries B. Wan J. Kane M.J. Mamsa H. Schäfer R. Stam A.H. Haan J. de Jong P.T. Storimans C.W. van Schooneveld M.J. Oosterhuis J.A. Gschwendter A. Dichgans M. Kotschet K.E. Hodgkinson S. Hardy T.A. Delatycki M.B. Hajj-Ali R.A. Kothari P.H. Nelson S.F. Frants R.R. Baloh R.W. Ferrari M.D. Atkinson J.P. et al.C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy.Nat. Genet. 2007; 39: 1068-1070Crossref PubMed Scopus (317) Google Scholar, 23.Lee-Kirsch M.A. Gong M. Chowdhury D. Senenko L. Engel K. Lee Y.A. de Silva U. Bailey S.L. Witte T. Vyse T.J. Kere J. Pfeiffer C. Harvey S. Wong A. Koskenmies S. Hummel O. Rohde K. Schmidt R.E. Dominiczak A.F. Gahr M. Hollis T. Perrino F.W. Lieberman J. Hübner N. et al.Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus.Nat. Genet. 2007; 39: 1065-1067Crossref PubMed Scopus (522) Google Scholar, 26.de Silva U. Choudhury S. Bailey S.L. Harvey S. Perrino F.W. Hollis T. et al.The crystal structure of TREX1 explains the 3′ nucleotide specificity and reveals a polyproline II helix for protein partnering.J. Biol. Chem. 2007; 282: 10537-10543Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). The TREX1 exonuclease degrades ssDNA polynucleotides and the nicked polynucleotide strands of dsDNA molecules with catalytic efficiencies that approach enzymatic limits (7.Mazur D.J. Perrino F.W. et al.Excision of 3′ termini by the Trex1 and TREX2 3′→5′ exonucleases. Characterization of the recombinant proteins.J. Biol. Chem. 2001; 276: 17022-17029Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 27.Harrigan J.A. Fan J. Momand J. Perrino F.W. Bohr V.A. Wilson D.M. et al.WRN exonuclease activity is blocked by DNA termini harboring 3′ obstructive groups.Mech. Ageing Dev. 2007; 128: 259-266Crossref PubMed Scopus (28) Google Scholar, 28.Lehtinen D.A. Harvey S. Mulcahy M.J. Hollis T. Perrino F.W. et al.The TREX1 double-stranded DNA degradation activity is defective in dominant mutations associated with autoimmune disease.J. Biol. Chem. 2008; 283: 31649-31656Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). The TREX1 mutant enzymes that cause human disease exhibit a broad range of DNA degradation activities that vary from levels indistinguishable from WT to those diminished by more than five orders of magnitude, with the levels of diminished activities being dependent upon DNA structure (13.Lee-Kirsch M.A. Chowdhury D. Harvey S. Gong M. Senenko L. Engel K. Pfeiffer C. Hollis T. Gahr M. Perrino F.W. Lieberman J. Hubner N. et al.A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus.J. Mol. Med. 2007; 85: 531-537Crossref PubMed Scopus (171) Google Scholar, 14.Rice G. Patrick T. Parmar R. Taylor C.F. Aeby A. Aicardi J. Artuch R. et al.Clinical and molecular phenotype of aicardi-goutieres syndrome.Am. J. Hum. Genet. 2007; 81: 713-725Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar, 20.Richards A. van den Maagdenberg A.M. Jen J.C. Kavanagh D. Bertram P. Spitzer D. Liszewski M.K. Barilla-Labarca M.L. Terwindt G.M. Kasai Y. McLellan M. Grand M.G. Vanmolkot K.R. de Vries B. Wan J. Kane M.J. Mamsa H. Schäfer R. Stam A.H. Haan J. de Jong P.T. Storimans C.W. van Schooneveld M.J. Oosterhuis J.A. Gschwendter A. Dichgans M. Kotschet K.E. Hodgkinson S. Hardy T.A. Delatycki M.B. Hajj-Ali R.A. Kothari P.H. Nelson S.F. Frants R.R. Baloh R.W. Ferrari M.D. Atkinson J.P. et al.C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy.Nat. Genet. 2007; 39: 1068-1070Crossref PubMed Scopus (317) Google Scholar, 23.Lee-Kirsch M.A. Gong M. Chowdhury D. Senenko L. Engel K. Lee Y.A. de Silva U. Bailey S.L. Witte T. Vyse T.J. Kere J. Pfeiffer C. Harvey S. Wong A. Koskenmies S. Hummel O. Rohde K. Schmidt R.E. Dominiczak A.F. Gahr M. Hollis T. Perrino F.W. Lieberman J. Hübner N. et al.Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus.Nat. Genet. 2007; 39: 1065-1067Crossref PubMed Scopus (522) Google Scholar, 28.Lehtinen D.A. Harvey S. Mulcahy M.J. Hollis T. Perrino F.W. et al.The TREX1 double-stranded DNA degradation activity is defective in dominant mutations associated with autoimmune disease.J. Biol. Chem. 2008; 283: 31649-31656Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 29.Orebaugh C.D. Fye J.M. Harvey S. Hollis T. Perrino F.W. et al.The TREX1 exonuclease R114H mutation in Aicardi-Goutieres syndrome and lupus reveals dimeric structure requirements for DNA degradation activity.J. Biol. Chem. 2011; 286: 40246-40254Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar30.Fye J.M. Orebaugh C.D. Coffin S.R. Hollis T. Perrino F.W. et al.Dominant mutation of the TREX1 exonuclease gene in lupus and Aicardi-Goutieres syndrome.J. Biol. Chem. 2011; 286: 32373-32382Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). The specific TREX1 disease-causing mutations can result in either diminished catalytic function or altered post-translational modification and cellular localization (20.Richards A. van den Maagdenberg A.M. Jen J.C. Kavanagh D. Bertram P. Spitzer D. Liszewski M.K. Barilla-Labarca M.L. Terwindt G.M. Kasai Y. McLellan M. Grand M.G. Vanmolkot K.R. de Vries B. Wan J. Kane M.J. Mamsa H. Schäfer R. Stam A.H. Haan J. de Jong P.T. Storimans C.W. van Schooneveld M.J. Oosterhuis J.A. Gschwendter A. Dichgans M. Kotschet K.E. Hodgkinson S. Hardy T.A. Delatycki M.B. Hajj-Ali R.A. Kothari P.H. Nelson S.F. Frants R.R. Baloh R.W. Ferrari M.D. Atkinson J.P. et al.C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy.Nat. Genet. 2007; 39: 1068-1070Crossref PubMed Scopus (317) Google Scholar, 23.Lee-Kirsch M.A. Gong M. Chowdhury D. Senenko L. Engel K. Lee Y.A. de Silva U. Bailey S.L. Witte T. Vyse T.J. Kere J. Pfeiffer C. Harvey S. Wong A. Koskenmies S. Hummel O. Rohde K. Schmidt R.E. Dominiczak A.F. Gahr M. Hollis T. Perrino F.W. Lieberman J. Hübner N. et al.Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus.Nat. Genet. 2007; 39: 1065-1067Crossref PubMed Scopus (522) Google Scholar, 31.Orebaugh C.D. Fye J.M. Harvey S. Hollis T. Wilkinson J.C. Perrino F.W. et al.The TREX1 C-terminal region controls cellular localization through ubiquitination.J. Biol. Chem. 2013; 288: 28881-28892Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). These varied effects exhibited by TREX1 mutant enzymes on catalytic function and cellular localization might be reconciled with the diversity of human disease pathogenesis to help explain the precise role of TREX1 in DNA degradation to prevent inappropriate immune activation. The TREX1 enzyme has a uniquely stable dimeric structure that is relevant to its function and to disease mechanisms in individuals carrying mutant alleles. The TREX1 R114H is one of the most frequently found mutations that causes AGS in homozygous and compound heterozygous genotypes and is found as a heterozygous mutation in systemic lupus erythematosus (8.Crow Y.J. Hayward B.E. Parmar R. Robins P. Leitch A. Ali M. Black D.N. van Bokhoven H. Brunner H.G. Hamel B.C. Corry P.C. Cowan F.M. Frints S.G. Klepper J. Livingston J.H. Lynch S.A. Massey R.F. Meritet J.F. Michaud J.L. Ponsot G. Voit T. Lebon P. Bonthron D.T. Jackson A.P. Barnes D.E. Lindahl T. et al.Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus.Nat. Genet. 2006; 38: 917-920Crossref PubMed Scopus (657) Google Scholar, 14.Rice G. Patrick T. Parmar R. Taylor C.F. Aeby A. Aicardi J. Artuch R. et al.Clinical and molecular phenotype of aicardi-goutieres syndrome.Am. J. Hum. Genet. 2007; 81: 713-725Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar, 17.Crow Y.J. Rehwinkel J. et al.Aicardi-Goutieres syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity.Hum. Mol. Genet. 2009; 18: R130-136Crossref PubMed Scopus (237) Google Scholar, 25.Namjou B. Kothari P.H. Kelly J.A. Glenn S.B. Ojwang J.O. Adler A. Alarcón-Riquelme M.E. Gallant C.J. Boackle S.A. Criswell L.A. Kimberly R.P. Brown E. Edberg J. Stevens A.M. Jacob C.O. Tsao B.P. Gilkeson G.S. Kamen D.L. Merrill J.T. Petri M. Goldman R.R. Vila L.M. Anaya J.M. Niewold T.B. Martin J. Pons-Estel B.A. Sabio J.M. Callejas J.L. Vyse T.J. Bae S.C. Perrino F.W. Freedman B.I. Scofield R.H. Moser K.L. Gaffney P.M. James J.A. Langefeld C.D. Kaufman K.M. Harley J.B. Atkinson J.P. et al.Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort.Genes Immun. 2011; 12: 270-279Crossref PubMed Scopus (207) Google Scholar). The TREX1 Arg-114 residue is ∼15 Å away from the active site and forms side chain-backbone interactions across the dimer interface, contributing to the catalytic function of the opposing protomer and helping to explain the immune dysfunction phenotype in the R114H heterozygous individual (28.Lehtinen D.A. Harvey S. Mulcahy M.J. Hollis T. Perrino F.W. et al.The TREX1 double-stranded DNA degradation activity is defective in dominant mutations associated with autoimmune disease.J. Biol. Chem. 2008; 283: 31649-31656Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 29.Orebaugh C.D. Fye J.M. Harvey S. Hollis T. Perrino F.W. et al.The TREX1 exonuclease R114H mutation in Aicardi-Goutieres syndrome and lupus reveals dimeric structure requirements for DNA degradation activity.J. Biol. Chem. 2011; 286: 40246-40254Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). The stable dimeric structure contributes to the FCL and AGS-dominant disease phenotypes in the TREX1 Asp-18 and Asp-200 active site mutations through the actions of a catalytically deficient protomer that retains DNA binding proficiency and blocks access to the DNA by TREX1WT enzyme (28.Lehtinen D.A. Harvey S. Mulcahy M.J. Hollis T. Perrino F.W. et al.The TREX1 double-stranded DNA degradation activity is defective in dominant mutations associated with autoimmune disease.J. Biol. Chem. 2008; 283: 31649-31656Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 30.Fye J.M. Orebaugh C.D. Coffin S.R. Hollis T. Perrino F.W. et al.Dominant mutation of the TREX1 exonuclease gene in lupus and Aicardi-Goutieres syndrome.J. Biol. Chem. 2011; 286: 32373-32382Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). Additionally, heterozygous TREX1 mutations in systemic lupus erythematosus (23.Lee-Kirsch M.A. Gong M. Chowdhury D. Senenko L. Engel K. Lee Y.A. de Silva U. Bailey S.L. Witte T. Vyse T.J. Kere J. Pfeiffer C. Harvey S. Wong A. Koskenmies S. Hummel O. Rohde K. Schmidt R.E. Dominiczak A.F. Gahr M. Hollis T. Perrino F.W. Lieberman J. Hübner N. et al.Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus.Nat. Genet. 2007; 39: 1065-1067Crossref PubMed Scopus (522) Google Scholar, 25.Namjou B. Kothari P.H. Kelly J.A. Glenn S.B. Ojwang J.O. Adler A. Alarcón-Riquelme M.E. Gallant C.J. Boackle S.A. Criswell L.A. Kimberly R.P. Brown E. Edberg J. Stevens A.M. Jacob C.O. Tsao B.P. Gilkeson G.S. Kamen D.L. Merrill J.T. Petri M. Goldman R.R. Vila L.M. Anaya J.M. Niewold T.B. Martin J. Pons-Estel B.A. Sabio J.M. Callejas J.L. Vyse T.J. Bae S.C. Perrino F.W. Freedman B.I. Scofield R.H. Moser K.L. Gaffney P.M. James J.A. Langefeld C.D. Kaufman K.M. Harley J.B. Atkinson J.P. et al.Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort.Genes Immun. 2011; 12: 270-279Crossref PubMed Scopus (207) Google Scholar) and retinal vasculopathy with cerebral leukodystrophy (20.Richards A. van den Maagdenberg A.M. Jen J.C. Kavanagh D. Bertram P. Spitzer D. Liszewski M.K. Barilla-Labarca M.L. Terwindt G.M. Kasai Y. McLellan M. Grand M.G. Vanmolkot K.R. de Vries B. Wan J. Kane M.J. Mamsa H. Schäfer R. Stam A.H. Haan J. de Jong P.T. Storimans C.W. van Schooneveld M.J. Oosterhuis J.A. Gschwendter A. Dichgans M. Kotschet K.E. Hodgkinson S. Hardy T.A. Delatycki M.B. Hajj-Ali R.A. Kothari P.H. Nelson S.F. Frants R.R. Baloh R.W. Ferrari M.D. Atkinson J.P. et al.C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy.Nat. Genet. 2007; 39: 1068-1070Crossref PubMed Scopus (317) Google Scholar) locate outside the catalytic domain in the C-terminal region potentially leading to dominant non-catalytic dysfunction related to cellular localization or protein interactions exacerbated by the stability of the dimer structure. The relevance of TREX1 structure and biochemistry to nucleic acid-mediated disease prompted the studies presented here to better understand the relationships between TREX1 mutation and disease phenotype. In addition to Arg-114, the TREX1 structure reveals residues positioned at the dimer interface such as Arg-62 that have not yet been identified as positions of disease-causing mutations but might contribute to enzyme activity through inter-protomer coordination (26.de Silva U. Choudhury S. Bailey S.L. Harvey S. Perrino F.W. Hollis T. et al.The crystal structure of TREX1 explains the 3′ nucleotide specificity and reveals a polyproline II helix for protein partnering.J. Biol. Chem. 2007; 282: 10537-10543Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 32.Bailey S.L. Harvey S. Perrino F.W. Hollis T. et al.Defects in DNA degradation revealed in crystal structures of TREX1 exonuclease mutations linked to autoimmune disease.DNA Repair. 2012; 11: 65-73Crossref PubMed Scopus (18) Google Scholar). The studies here test the hypothesis that the conserved TREX1 Arg-62 residues extend across the dimer interface and contribute to catalysis in the active site of the opposing protomer specifically through DNA binding. The activities of TREX1 R62A-containing homodimers, heterodimers, and compound heterodimers were compared with TREX1WT using quantitative ss- and dsDNA degradation assays. The DNA degradation activities and DNA binding measured in the TREX1 R62A-containing mutants demonstrate that Arg-62 from one TREX1 protomer contributes to DNA degradation in the opposing protomer. These results show that the mechanism of the TREX1 Arg-62 “across the dimer interface” contribution is through DNA binding in the opposing protomer. The synthetic 30-mer oligonucleotide 5′-ATACGACGGTGACAGTGTTGTCAGACAGGT-3′ with 5′-fluorescein was from Operon. The plasmid derived from p-MYC (New England Biolabs) contained one Nt.BbvCI site, and the pUC57 plasmid (Genewiz) contained one Nt.Bsp.QI site. The plasmids were purified from bacterial cultures using Qiagen kits. The singly nicked dsDNA oligonucleotide used for equilibrium-binding studies was constructed by annealing a synthetic 90-mer to two complementary 45-mer oligonucleotides (Operon). The 90-mer and the 3′-positioned 45-mer contained 3′-phosphate groups to block TREX1 and the 5′-positioned 45-mer contained a 5′-FAM or was unlabeled. Oligonucleotides were annealed in 5 mm MES (pH 6.5), 20 mm NaCl, and 5 mm MgCl2 to generate the singly nicked dsDNA oligonucleotide. The human recombinant TREX1 enzymes were expressed in bacteria and purified as stable homo- or heterodimers as described (28.Lehtinen D.A. Harvey S. Mulcahy M.J. Hollis T. Perrino F.W. et al.The TREX1 double-stranded DNA degradation activity is defective in dominant mutations associated with autoimmune disease.J. Biol. Chem. 2008; 283: 31649-31656Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 29.Orebaugh C.D. Fye J.M. Harvey S. Hollis T. Perrino F.W. et al.The TREX1 exonuclease R114H mutation in Aicardi-Goutieres syndrome and lupus reveals dimeric structure requirements for DNA degradation activity.J. Biol. Chem. 2011; 286: 40246-40254Abstract" @default.
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• W2014207515 title "The Arg-62 Residues of the TREX1 Exonuclease Act Across the Dimer Interface Contributing to Catalysis in the Opposing Protomers" @default.
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