|3aaf, resolution 1.90Å ()|
Structure of WRN RQC domain bound to double-stranded DNA
The RecQ family of DNA helicases including WRN (Werner syndrome protein) and BLM (Bloom syndrome protein) protects the genome against deleterious changes. Here we report the cocrystal structure of the RecQ C-terminal (RQC) domain of human WRN bound to a DNA duplex. In the complex, the RQC domain specifically interacted with a blunt end of the duplex and, surprisingly, unpaired a Watson-Crick base pair in the absence of an ATPase domain. The beta wing, an extended hairpin motif that is characteristic of winged-helix motifs, was used as a "separating knife" to wedge between the first and second base pairs, whereas the recognition helix, a principal component of helix-turn-helix motifs that are usually embedded within DNA grooves, was unprecedentedly excluded from the interaction. Our results demonstrate a function of the winged-helix motif central to the helicase reaction, establishing the first structural paradigm concerning the DNA structure-specific activities of the RecQ helicases.
Structural basis for DNA strand separation by the unconventional winged-helix domain of RecQ helicase WRN., Kitano K, Kim SY, Hakoshima T, Structure. 2010 Feb 10;18(2):177-87. PMID:20159463
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[WRN_HUMAN] Defects in WRN are a cause of Werner syndrome (WRN) [MIM:277700]. WRN is a rare autosomal recessive progeroid syndrome characterized by the premature onset of multiple age-related disorders, including atherosclerosis, cancer, non-insulin-dependent diabetes mellitus, ocular cataracts and osteoporosis. The major cause of death, at a median age of 47, is myocardial infarction. Currently all known WS mutations produces prematurely terminated proteins. Defects in WRN may be a cause of colorectal cancer (CRC) [MIM:114500].
[WRN_HUMAN] Multifunctional enzyme that has both magnesium and ATP-dependent DNA-helicase activity and 3'->5' exonuclease activity towards double-stranded DNA with a 5'-overhang. Has no nuclease activity towards single-stranded DNA or blunt-ended double-stranded DNA. Binds preferentially to DNA substrates containing alternate secondary structures, such as replication forks and Holliday junctions. May play an important role in the dissociation of joint DNA molecules that can arise as products of homologous recombination, at stalled replication forks or during DNA repair. Alleviates stalling of DNA polymerases at the site of DNA lesions. Important for genomic integrity. Plays a role in the formation of DNA replication focal centers; stably associates with foci elements generating binding sites for RP-A (By similarity).
About this Structure
- Kitano K, Kim SY, Hakoshima T. Structural basis for DNA strand separation by the unconventional winged-helix domain of RecQ helicase WRN. Structure. 2010 Feb 10;18(2):177-87. PMID:20159463 doi:10.1016/j.str.2009.12.011
- ↑ Huang S, Lee L, Hanson NB, Lenaerts C, Hoehn H, Poot M, Rubin CD, Chen DF, Yang CC, Juch H, Dorn T, Spiegel R, Oral EA, Abid M, Battisti C, Lucci-Cordisco E, Neri G, Steed EH, Kidd A, Isley W, Showalter D, Vittone JL, Konstantinow A, Ring J, Meyer P, Wenger SL, von Herbay A, Wollina U, Schuelke M, Huizenga CR, Leistritz DF, Martin GM, Mian IS, Oshima J. The spectrum of WRN mutations in Werner syndrome patients. Hum Mutat. 2006 Jun;27(6):558-67. PMID:16673358 doi:10.1002/humu.20337
- ↑ Xue Y, Ratcliff GC, Wang H, Davis-Searles PR, Gray MD, Erie DA, Redinbo MR. A minimal exonuclease domain of WRN forms a hexamer on DNA and possesses both 3'- 5' exonuclease and 5'-protruding strand endonuclease activities. Biochemistry. 2002 Mar 5;41(9):2901-12. PMID:11863428
- ↑ Kamath-Loeb AS, Lan L, Nakajima S, Yasui A, Loeb LA. Werner syndrome protein interacts functionally with translesion DNA polymerases. Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10394-9. Epub 2007 Jun 11. PMID:17563354 doi:10.1073/pnas.0702513104
- ↑ Compton SA, Tolun G, Kamath-Loeb AS, Loeb LA, Griffith JD. The Werner syndrome protein binds replication fork and holliday junction DNAs as an oligomer. J Biol Chem. 2008 Sep 5;283(36):24478-83. doi: 10.1074/jbc.M803370200. Epub 2008 , Jul 2. PMID:18596042 doi:10.1074/jbc.M803370200
- ↑ Zecevic A, Menard H, Gurel V, Hagan E, DeCaro R, Zhitkovich A. WRN helicase promotes repair of DNA double-strand breaks caused by aberrant mismatch repair of chromium-DNA adducts. Cell Cycle. 2009 Sep 1;8(17):2769-78. Epub 2009 Sep 2. PMID:19652551
- ↑ Opresko PL, Sowd G, Wang H. The Werner syndrome helicase/exonuclease processes mobile D-loops through branch migration and degradation. PLoS One. 2009;4(3):e4825. doi: 10.1371/journal.pone.0004825. Epub 2009 Mar 13. PMID:19283071 doi:10.1371/journal.pone.0004825