Regulation of Mre11/Rad50 by Nbs1: effects on nucleotide-dependent DNA binding and association with ataxia-telangiectasia-like disorder mutant complexes - PubMed (original) (raw)
. 2003 Nov 14;278(46):45171-81.
doi: 10.1074/jbc.M308705200. Epub 2003 Sep 8.
Affiliations
- PMID: 12966088
- DOI: 10.1074/jbc.M308705200
Free article
Regulation of Mre11/Rad50 by Nbs1: effects on nucleotide-dependent DNA binding and association with ataxia-telangiectasia-like disorder mutant complexes
Ji-Hoon Lee et al. J Biol Chem. 2003.
Free article
Abstract
The Mre11/Rad50 complex is a critical component of the cellular response to DNA double-strand breaks, in organisms ranging from archaebacteria to humans. In mammalian cells, Mre11/Rad50 (M/R) associates with a third component, Nbs1, that regulates its activities and is targeted by signaling pathways that initiate DNA damage-induced checkpoint responses. Mutations in the genes that encode Nbs1 and Mre11 are responsible for the human radiation sensitivity disorders Nijmegen breakage syndrome (NBS) and ataxia-telangiectasia-like disorder (ATLD), respectively, which are characterized by defective checkpoint responses and high levels of chromosomal abnormalities. Here we demonstrate nucleotide-dependent DNA binding by the human M/R complex that requires the Nbs1 protein and is specific for double-strand DNA duplexes. Efficient DNA binding is only observed with non-hydrolyzable analogs of ATP, suggesting that ATP hydrolysis normally effects DNA release. The alleles of MRE11 associated with ATLD and the C-terminal Nbs1 polypeptide associated with NBS were expressed with the other components and found to form triple complexes except in the case of ATLD 3/4, which exhibits variability in Nbs1 association. The ATLD 1/2, ATLD 3/4, and p70 M/R/N complexes exhibit nucleotide-dependent DNA binding and exonuclease activity equivalent to the wild-type enzyme, although the ATLD complexes both show reduced activity in endonuclease assays. Sedimentation equilibrium analysis of the recombinant human complexes indicates that Mre11 is a stable dimer, Mre11 and Nbs1 form a 1:1 complex, and both M/R and M/R/N form large multimeric assemblies of approximately 1.2 MDa. Models of M/R/N stoichiometry in light of this and previous data are discussed.
Similar articles
- Molecular characterization of the Schizosaccharomyces pombe nbs1+ gene involved in DNA repair and telomere maintenance.
Ueno M, Nakazaki T, Akamatsu Y, Watanabe K, Tomita K, Lindsay HD, Shinagawa H, Iwasaki H. Ueno M, et al. Mol Cell Biol. 2003 Sep;23(18):6553-63. doi: 10.1128/MCB.23.18.6553-6563.2003. Mol Cell Biol. 2003. PMID: 12944481 Free PMC article. - The fission yeast Rad32 (Mre11)-Rad50-Nbs1 complex is required for the S-phase DNA damage checkpoint.
Chahwan C, Nakamura TM, Sivakumar S, Russell P, Rhind N. Chahwan C, et al. Mol Cell Biol. 2003 Sep;23(18):6564-73. doi: 10.1128/MCB.23.18.6564-6573.2003. Mol Cell Biol. 2003. PMID: 12944482 Free PMC article. - Arsenic-induced Mre11 phosphorylation is cell cycle-dependent and defective in NBS cells.
Yuan SS, Su JH, Hou MF, Yang FW, Zhao S, Lee EY. Yuan SS, et al. DNA Repair (Amst). 2002 Feb 28;1(2):137-42. doi: 10.1016/s1568-7864(01)00009-x. DNA Repair (Amst). 2002. PMID: 12509260 - Ataxia-telangiectasia-like disorder (ATLD)-its clinical presentation and molecular basis.
Taylor AM, Groom A, Byrd PJ. Taylor AM, et al. DNA Repair (Amst). 2004 Aug-Sep;3(8-9):1219-25. doi: 10.1016/j.dnarep.2004.04.009. DNA Repair (Amst). 2004. PMID: 15279810 Review.
Cited by
- The MRE11-RAD50-NBS1 complex both starts and extends DNA end resection in mouse meiosis.
Kim S, Yamada S, Li T, Canasto-Chibuque C, Kim JH, Marcet-Ortega M, Xu J, Eng DY, Feeney L, Petrini JHJ, Keeney S. Kim S, et al. bioRxiv [Preprint]. 2024 Aug 17:2024.08.17.608390. doi: 10.1101/2024.08.17.608390. bioRxiv. 2024. PMID: 39185212 Free PMC article. Preprint. - Binding of the TRF2 iDDR motif to RAD50 highlights a convergent evolutionary strategy to inactivate MRN at telomeres.
Khayat F, Alshmery M, Pal M, Oliver AW, Bianchi A. Khayat F, et al. Nucleic Acids Res. 2024 Jul 22;52(13):7704-7719. doi: 10.1093/nar/gkae509. Nucleic Acids Res. 2024. PMID: 38884214 Free PMC article. - SPRTN protease-cleaved MRE11 decreases DNA repair and radiosensitises cancer cells.
Na J, Newman JA, Then CK, Syed J, Vendrell I, Torrecilla I, Ellermann S, Ramadan K, Fischer R, Kiltie AE. Na J, et al. Cell Death Dis. 2021 Feb 8;12(2):165. doi: 10.1038/s41419-021-03437-w. Cell Death Dis. 2021. PMID: 33558481 Free PMC article. - A Survey of Reported Disease-Related Mutations in the MRE11-RAD50-NBS1 Complex.
Rahman S, Canny MD, Buschmann TA, Latham MP. Rahman S, et al. Cells. 2020 Jul 13;9(7):1678. doi: 10.3390/cells9071678. Cells. 2020. PMID: 32668560 Free PMC article. Review. - MRE11 UFMylation promotes ATM activation.
Wang Z, Gong Y, Peng B, Shi R, Fan D, Zhao H, Zhu M, Zhang H, Lou Z, Zhou J, Zhu WG, Cong YS, Xu X. Wang Z, et al. Nucleic Acids Res. 2019 May 7;47(8):4124-4135. doi: 10.1093/nar/gkz110. Nucleic Acids Res. 2019. PMID: 30783677 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Research Materials
Miscellaneous