Crystal Structure of the First Eubacterial Mre11 Nuclease Reveals Novel Features that May Discriminate Substrates During DNA Repair

被引：31

作者：

Das, Debanu ^{[2
]}

Moiani, Davide ^{[1
,3
]}

Axelrod, Herbert L. ^{[2
]}

Miller, Mitchell D. ^{[2
]}

McMullan, Daniel ^{[4
]}

Jin, Kevin K. ^{[2
]}

Abdubek, Polat ^{[4
]}

Astakhova, Tamara ^{[5
]}

Burra, Prasad ^{[6
]}

Carlton, Dennis ^{[1
]}

Chiu, Hsiu-Ju ^{[2
]}

Clayton, Thomas ^{[1
]}

Deller, Marc C. ^{[1
]}

Duan, Lian ^{[5
]}

Ernst, Dustin ^{[4
]}

Feuerhelm, Julie ^{[4
]}

Grant, Joanna C. ^{[4
]}

Grzechnik, Anna ^{[1
]}

Grzechnik, Slawomir K. ^{[5
]}

Han, Gye Won ^{[1
]}

Jaroszewski, Lukasz ^{[5
,6
]}

Klock, Heath E. ^{[4
]}

Knuth, Mark W. ^{[4
]}

Kozbial, Piotr ^{[6
]}

Krishna, S. Sri ^{[5
,6
]}

Kumar, Abhinav ^{[2
]}

Marciano, David ^{[1
]}

Morse, Andrew T. ^{[5
]}

Nigoghossian, Edward ^{[4
]}

Okach, Linda ^{[4
]}

Paulsen, Jessica ^{[4
]}

Reyes, Ron ^{[2
]}

Rife, Christopher L. ^{[2
]}

Sefcovic, Natasha ^{[6
]}

Tien, Henry J. ^{[1
]}

Trame, Christine B. ^{[2
]}

van den Bedem, Henry ^{[2
]}

Weekes, Dana ^{[6
]}

Xu, Qingping ^{[2
]}

Hodgson, Keith O.

Wooley, John ^{[5
]}

Elsliger, Marc-Andre ^{[1
]}

Deacon, Ashley M. ^{[2
]}

Godzik, Adam ^{[5
,6
]}

Lesley, Scott A. ^{[1
,4
]}

Tainer, John A. ^{[1
,3
,7
]}

Wilson, Ian A. ^{[1
]}

机构：

[1] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA

[2] SLAC Natl Accelerator Lab, Stanford Synchrotron Radiat Lightsource, Menlo Pk, CA 94025 USA

[3] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA

[4] Novartis Res Fdn, Prot Sci Dept, Genom Inst, San Diego, CA 92121 USA

[5] Univ Calif San Diego, Ctr Res Biol Syst, La Jolla, CA 92093 USA

[6] Burnham Inst Med Res, Prograrn Bioinformat & Syst Biol, La Jolla, CA 92037 USA

[7] Univ Calif Berkeley, Lawrence Berkeley Lab, Dept Mol Biol, Div Life Sci, Berkeley, CA 94720 USA

来源：

JOURNAL OF MOLECULAR BIOLOGY | 2010年 / 397卷 / 03期

基金：

美国国家卫生研究院;

关键词：

Mre11; nuclease; DNA repair; crystal structure; structural genomics; DOUBLE-STRAND BREAKS; ESCHERICHIA-COLI; ATAXIA-TELANGIECTASIA; PROTEIN; COMPLEX; RECOMBINATION; DATABASE; SBCCD; MRE11-RAD50-NBS1; DIFFRACTION;

D O I：

10.1016/j.jmb.2010.01.049

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Mre11 nuclease plays a central role in the repair of cytotoxic and mutagenic DNA double-strand breaks. As X-ray structural information has been available only for the Pyrococcus furiosus enzyme (PfMre11), the conserved and variable features of this nuclease across the domains of life have not been experimentally defined. Our crystal structure and biochemical studies demonstrate that TM1635 from Thermotoga maritima, originally annotated as a putative nuclease, is an Mre11 endo/exonuclease (TmMre11) and the first such structure from eubacteria. TmMre11 and PfMre11 display similar overall structures, despite sequence identity in the twilight zone of only similar to 20%. However, they differ substantially in their DNA-specificity domains and in their dimeric organization. Residues in the nuclease domain are highly conserved, but those in the DNA-specificity domain are not. The structural differences likely affect how Mre11 from different organisms recognize and interact with single-stranded DNA, double-stranded DNA and DNA hairpin structures during DNA repair. The TmMre11 nuclease active site has no bound metal ions, but is conserved in sequence and structure with the exception of a histidine that is important in PfMre11 nuclease activity. Nevertheless, biochemical characterization confirms that TmMre11 possesses both endonuclease and exonuclease activities on single-stranded and double-stranded DNA substrates, respectively. (c) 2010 Elsevier Ltd. All rights reserved.

引用

页码：647 / 663

页数：17

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