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Structural highlights
| 7rds is a 1 chain structure with sequence from Homo sapiens. hNTHL1 has two domains connected with two linkers. Domain 1 has the FeS cluster, the N-terminus, the C-terminus and one catalytic residue (Asp). The second domain has the other catalytic resudye (Lys),a six-helical barrel domain, and a HhH motif. It is captured in an open conformation with a conformational change being required for the catalytic residues to assembled. [1]
Domains
Role of FeS
HhH role
Flexible linker...
| | Method: | X-ray diffraction, Resolution 2.5Å |
| Ligands: | |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
NTH_HUMAN NTHL1-Tumor Syndrome is a disease is caused by variants affecting the gene represented in this entry. This syndrome is characterized by an increased risk of colorrectal cancer, breast cancer, and colorectal polyposis. Being diagnoised with the germline biallelic pathogenic variant, through molecular genetic testing, increases ones cumulative lifetime risk of developing extracolonic cancer by age 60 from 45-78%. Upon diagnoises colorectal poylpops should be removed until the size and density of the polpos cannot be damaged. At this point either subtotal colectomy or protcolectomy (partial or full remove of the colon) should be prefomed. Around 5% of colorrectal cancers can be explained by germline mutations within a CRC predipsoing gene. Exome sequencing has lead to the identification of a a homozygous nonsense mutation (c.268C>T encoding p.Q90*) in the base excision repair gene NTHL1 in three unrelated families. [HAMAP-Rule:MF_03183][2]. [3]
Other Diseases Releated breast...more on previous source
Upregulation by transcription fueling cancers...BCLAA
Function
NTH_HUMAN Bifunctional DNA N-glycosylase with associated apurinic/apyrimidinic (AP) lyase function that catalyzes the first step in base excision repair (BER), the primary repair pathway for the repair of oxidative DNA damage (PubMed:9927729). The DNA N-glycosylase activity releases the damaged DNA base from DNA by cleaving the N-glycosidic bond, leaving an AP site. The AP-lyase activity cleaves the phosphodiester bond 3' to the AP site by a beta-elimination. Primarily recognizes and repairs oxidative base damage of pyrimidines. Has also 8-oxo-7,8-dihydroguanine (8-oxoG) DNA glycosylase activity. Acts preferentially on DNA damage opposite guanine residues in DNA. Is able to process lesions in nucleosomes without requiring or inducing nucleosome disruption.[HAMAP-Rule:MF_03183][4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21]
Relevance
Publication Abstract from PubMed
Base excision repair (BER) is the main pathway protecting cells from the continuous damage to DNA inflicted by reactive oxygen species. BER is initiated by DNA glycosylases, each of which repairs a particular class of base damage. NTHL1, a bifunctional DNA glycosylase, possesses both glycolytic and beta-lytic activities with a preference for oxidized pyrimidine substrates. Defects in human NTHL1 drive a class of polyposis colorectal cancer. We report the first X-ray crystal structure of hNTHL1, revealing an open conformation not previously observed in the bacterial orthologs. In this conformation, the six-helical barrel domain comprising the helix-hairpin-helix (HhH) DNA binding motif is tipped away from the iron sulphur cluster-containing domain, requiring a conformational change to assemble a catalytic site upon DNA binding. We found that the flexibility of hNTHL1 and its ability to adopt an open configuration can be attributed to an interdomain linker. Swapping the human linker sequence for that of Escherichia coli yielded a protein chimera that crystallized in a closed conformation and had a reduced activity on lesion-containing DNA. This large scale interdomain rearrangement during catalysis is unprecedented for a HhH superfamily DNA glycosylase and provides important insight into the molecular mechanism of hNTHL1.
Caught in motion: human NTHL1 undergoes interdomain rearrangement necessary for catalysis.,Carroll BL, Zahn KE, Hanley JP, Wallace SS, Dragon JA, Doublie S Nucleic Acids Res. 2021 Dec 16;49(22):13165-13178. doi: 10.1093/nar/gkab1162. PMID:34871433[22]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Carroll BL, Zahn KE, Hanley JP, Wallace SS, Dragon JA, Doublié S. Caught in motion: human NTHL1 undergoes interdomain rearrangement necessary for catalysis. Nucleic Acids Res. 2021 Dec 16;49(22):13165-13178. PMID:34871433 doi:10.1093/nar/gkab1162
- ↑ De Voer RM, Nielsen M, Gao W, Kuiper RP, Hoogerbrugge N. NTHL1 Tumor Syndrome. PMID:32239880
- ↑ Weren RD, Ligtenberg MJ, Kets CM, de Voer RM, Verwiel ET, Spruijt L, van Zelst-Stams WA, Jongmans MC, Gilissen C, Hehir-Kwa JY, Hoischen A, Shendure J, Boyle EA, Kamping EJ, Nagtegaal ID, Tops BB, Nagengast FM, Geurts van Kessel A, van Krieken JH, Kuiper RP, Hoogerbrugge N. A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer. Nat Genet. 2015 Jun;47(6):668-71. PMID:25938944 doi:10.1038/ng.3287
- ↑ Luna L, Bjørås M, Hoff E, Rognes T, Seeberg E. Cell-cycle regulation, intracellular sorting and induced overexpression of the human NTH1 DNA glycosylase involved in removal of formamidopyrimidine residues from DNA. Mutat Res. 2000 Jul 25;460(2):95-104. PMID:10882850 doi:10.1016/s0921-8777(00)00015-x
- ↑ Matsumoto Y, Zhang QM, Takao M, Yasui A, Yonei S. Escherichia coli Nth and human hNTH1 DNA glycosylases are involved in removal of 8-oxoguanine from 8-oxoguanine/guanine mispairs in DNA. Nucleic Acids Res. 2001 May 1;29(9):1975-81. PMID:11328882 doi:10.1093/nar/29.9.1975
- ↑ Eide L, Luna L, Gustad EC, Henderson PT, Essigmann JM, Demple B, Seeberg E. Human endonuclease III acts preferentially on DNA damage opposite guanine residues in DNA. Biochemistry. 2001 Jun 5;40(22):6653-9. PMID:11380260 doi:10.1021/bi0028901
- ↑ Liu X, Roy R. Mutation at active site lysine 212 to arginine uncouples the glycosylase activity from the lyase activity of human endonuclease III. Biochemistry. 2001 Nov 13;40(45):13617-22. PMID:11695910 doi:10.1021/bi011053b
- ↑ Miyabe I, Zhang QM, Kino K, Sugiyama H, Takao M, Yasui A, Yonei S. Identification of 5-formyluracil DNA glycosylase activity of human hNTH1 protein. Nucleic Acids Res. 2002 Aug 1;30(15):3443-8. PMID:12140329 doi:10.1093/nar/gkf460
- ↑ Liu X, Roy R. Truncation of amino-terminal tail stimulates activity of human endonuclease III (hNTH1). J Mol Biol. 2002 Aug 9;321(2):265-76. PMID:12144783 doi:10.1016/s0022-2836(02)00623-x
- ↑ Marenstein DR, Chan MK, Altamirano A, Basu AK, Boorstein RJ, Cunningham RP, Teebor GW. Substrate specificity of human endonuclease III (hNTH1). Effect of human APE1 on hNTH1 activity. J Biol Chem. 2003 Mar 14;278(11):9005-12. PMID:12519758 doi:10.1074/jbc.M212168200
- ↑ Katafuchi A, Nakano T, Masaoka A, Terato H, Iwai S, Hanaoka F, Ide H. Differential specificity of human and Escherichia coli endonuclease III and VIII homologues for oxidative base lesions. J Biol Chem. 2004 Apr 2;279(14):14464-71. PMID:14734554 doi:10.1074/jbc.M400393200
- ↑ Zhang QM, Yonekura S, Takao M, Yasui A, Sugiyama H, Yonei S. DNA glycosylase activities for thymine residues oxidized in the methyl group are functions of the hNEIL1 and hNTH1 enzymes in human cells. DNA Repair (Amst). 2005 Jan 2;4(1):71-9. PMID:15533839 doi:10.1016/j.dnarep.2004.08.002
- ↑ Prasad A, Wallace SS, Pederson DS. Initiation of base excision repair of oxidative lesions in nucleosomes by the human, bifunctional DNA glycosylase NTH1. Mol Cell Biol. 2007 Dec;27(24):8442-53. PMID:17923696 doi:10.1128/MCB.00791-07
- ↑ Odell ID, Newick K, Heintz NH, Wallace SS, Pederson DS. Non-specific DNA binding interferes with the efficient excision of oxidative lesions from chromatin by the human DNA glycosylase, NEIL1. DNA Repair (Amst). 2010 Feb 4;9(2):134-43. PMID:20005182 doi:10.1016/j.dnarep.2009.11.005
- ↑ Matsumoto N, Toga T, Hayashi R, Sugasawa K, Katayanagi K, Ide H, Kuraoka I, Iwai S. Fluorescent probes for the analysis of DNA strand scission in base excision repair. Nucleic Acids Res. 2010 Apr;38(7):e101. PMID:20110254 doi:10.1093/nar/gkq022
- ↑ Odell ID, Barbour JE, Murphy DL, Della-Maria JA, Sweasy JB, Tomkinson AE, Wallace SS, Pederson DS. Nucleosome disruption by DNA ligase III-XRCC1 promotes efficient base excision repair. Mol Cell Biol. 2011 Nov;31(22):4623-32. PMID:21930793 doi:10.1128/MCB.05715-11
- ↑ Aspinwall R, Rothwell DG, Roldan-Arjona T, Anselmino C, Ward CJ, Cheadle JP, Sampson JR, Lindahl T, Harris PC, Hickson ID. Cloning and characterization of a functional human homolog of Escherichia coli endonuclease III. Proc Natl Acad Sci U S A. 1997 Jan 7;94(1):109-14. PMID:8990169 doi:10.1073/pnas.94.1.109
- ↑ Hilbert TP, Chaung W, Boorstein RJ, Cunningham RP, Teebor GW. Cloning and expression of the cDNA encoding the human homologue of the DNA repair enzyme, Escherichia coli endonuclease III. J Biol Chem. 1997 Mar 7;272(10):6733-40. PMID:9045706 doi:10.1074/jbc.272.10.6733
- ↑ Ikeda S, Biswas T, Roy R, Izumi T, Boldogh I, Kurosky A, Sarker AH, Seki S, Mitra S. Purification and characterization of human NTH1, a homolog of Escherichia coli endonuclease III. Direct identification of Lys-212 as the active nucleophilic residue. J Biol Chem. 1998 Aug 21;273(34):21585-93. PMID:9705289 doi:10.1074/jbc.273.34.21585
- ↑ Dizdaroglu M, Karahalil B, Sentürker S, Buckley TJ, Roldán-Arjona T. Excision of products of oxidative DNA base damage by human NTH1 protein. Biochemistry. 1999 Jan 5;38(1):243-6. PMID:9890904 doi:10.1021/bi9819071
- ↑ Bessho T. Nucleotide excision repair 3' endonuclease XPG stimulates the activity of base excision repairenzyme thymine glycol DNA glycosylase. Nucleic Acids Res. 1999 Feb 15;27(4):979-83. PMID:9927729 doi:10.1093/nar/27.4.979
- ↑ Carroll BL, Zahn KE, Hanley JP, Wallace SS, Dragon JA, Doublié S. Caught in motion: human NTHL1 undergoes interdomain rearrangement necessary for catalysis. Nucleic Acids Res. 2021 Dec 16;49(22):13165-13178. PMID:34871433 doi:10.1093/nar/gkab1162
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