User:Marcos Ngo/Sandbox 1

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]^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18]}

Structural highlights

hNTHL1 has which are connected by two linkers. has the iron sulfur cluster, N- and C-termini, and a catalytic resiude (asp). has six helical barrels, hairpin-helix-hairpin, and the final catalytic residue (gly). This structure is captured in an . A is required for the catalytic residues to assemble. Cluster

The role of the iron sulfur cluster is highly debated. One of main views it that the cluster is involved in scanning for lesions. Researchers found that oxidizing the FeS cluster in hNTHL1 from [4Fe-4S]^2+ to [4Fe-4S]^3+ increases its binding to DNA. When a mismatch such as C:A is introduced, this can disrupt DNA charge transport causing the reduction of the iron sulfur cluster to not occur leaving Nth bound. The proposed mechanism is that in undamaged DNA, electrons can travel along the helix and reduce the iron-sulfur cluster, lowering Nth’s affinity and allowing it to move on. But if CT is disrupted by damage, the cluster stays oxidized, keeping Nth bound at the site to continue searching for lesions. Another view is that the FeS cluster plays a role as a structural scaffold which is used for the stabilizing the interaction with DNA upon recognizing damage .

^[19][20][21]

</td></tr><tr id='method'><td class="sblockLbl">Method:</td><td class="sblockDat" id="methodDat">X-ray diffraction, Resolution 2.5Å</td></tr> <tr id='ligand'><td class="sblockLbl">Ligands:</td><td class="sblockDat" id="ligandDat"></td></tr> <tr id='resources'><td class="sblockLbl">Resources:</td><td class="sblockDat">FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT</td></tr> </table>

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]^[22]. ^[23]

Other Diseases Releated breast...more on previous source

Upregulation by transcription fueling cancers...BCLAA

References

1. ↑ 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
2. ↑ 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
3. ↑ 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
4. ↑ 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
5. ↑ 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
6. ↑ 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
7. ↑ 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
8. ↑ 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
9. ↑ 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
10. ↑ 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
11. ↑ 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
12. ↑ 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
13. ↑ 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
14. ↑ 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
15. ↑ 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
16. ↑ 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
17. ↑ 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
18. ↑ 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
19. ↑ Boal AK, Genereux JC, Sontz PA, Gralnick JA, Newman DK, Barton JK. Redox signaling between DNA repair proteins for efficient lesion detection. Proc Natl Acad Sci U S A. 2009 Sep 8;106(36):15237-42. PMID:19720997 doi:10.1073/pnas.0908059106
20. ↑ Tse ECM, Zwang TJ, Barton JK. The Oxidation State of [4Fe4S] Clusters Modulates the DNA-Binding Affinity of DNA Repair Proteins. J Am Chem Soc. 2017 Sep 13;139(36):12784-12792. PMID:28817778 doi:10.1021/jacs.7b07230
21. ↑ doi: https://dx.doi.org/https
22. ↑ De Voer RM, Nielsen M, Gao W, Kuiper RP, Hoogerbrugge N. NTHL1 Tumor Syndrome. PMID:32239880
23. ↑ 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