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The Structural and Functional Characterization of Human Recq4 Reveals Insights Into Its Helicase Mechanism

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The Structural and Functional Characterization of Human Recq4 Reveals Insights Into Its Helicase Mechanism ARTICLE Received 28 Oct 2016 | Accepted 11 May 2017 | Published 27 Jun 2017 DOI: 10.1038/ncomms15907 OPEN The structural and functional characterization of human RecQ4 reveals insights into its helicase mechanism Sebastian Kaiser1, Florian Sauer1 & Caroline Kisker1 RecQ4 is a member of the RecQ helicase family, an evolutionarily conserved class of enzymes, dedicated to preserving genomic integrity by operating in telomere maintenance, DNA repair and replication. While reduced RecQ4 activity is associated with cancer predisposition and premature aging, RecQ4 upregulation is related to carcinogenesis and metastasis. Within the RecQ family, RecQ4 assumes an exceptional position, lacking several characteristic RecQ domains. Here we present the crystal structure of human RecQ4, encompassing the conserved ATPase core and a novel C-terminal domain that lacks resemblance to the RQC domain observed in other RecQ helicases. The new domain features a zinc-binding site and two distinct types of winged-helix domains, which are not involved in canonical DNA binding or helicase activity. Based on our structural and functional analysis, we propose that RecQ4 exerts a helicase mechanism, which may be more closely related to bacterial RecQ helicases than to its human family members. 1 Rudolf-Virchow-Center for Experimental Biomedicine, Institute of Structural Biology, Josef-Schneider-Str. 2/D15, Wuerzburg 97080, Germany. Correspondence and requests for materials should be addressed to C.K. (email: [email protected]). NATURE COMMUNICATIONS | 8:15907 | DOI: 10.1038/ncomms15907 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms15907 reservation of genomic integrity is a prime objective for ssDNA/dsDNA junction. This observation led to the proposal every living organism to maintain cell homeostasis and to that bacterial RecQs might utilize a helicase mechanism, which is Ppass on conserved genetic information to the following based on a critical bend angle instead of a b-hairpin element to generation. The family of RecQ helicases has emerged as a vital destabilize base pairing15. Remarkably, RecQ4 entirely lacks the class of enzymes to ensure proper genome maintenance by RQC domain, yet its helicase activity is required for various DNA performing a broad variety of functions in DNA replication, protective functions16,17. This raises the question of how dsDNA recombination and repair as well as telomere stability1,2. RecQ separation is achieved in this important RecQ homologue. The third proteins are highly conserved from bacteria to humans and and least conserved structural element of the RecQ helicase family is impaired function leads to increased incidences of genomic the HRDC domain, which is only present in BLM and WRN as well fragility, chromosomal breakage and rearrangements, ultimately as in bacterial and yeast homologues18. The low sequence promoting carcinogenesis and accelerated aging in higher conservation of HRDC domains results in distinct surface organisms. Intriguingly, overexpression of RecQ helicases may properties, which were suggested to mediate unique protein also promote tumorigenesis and RecQ4 in particular is highly interactions of individual RecQ helicases, fine-tuning their upregulated in cervical, prostate and breast cancers3–5. Generally, distinctive cellular functions19,20. one RecQ homologue is found in single cellular organisms, The human recq4 gene encodes a 1208 amino acid (aa) whereas higher life forms express multiple paralogues. polypeptide, resulting in a 133 kDa protein with the highly On the basis of homology to the ATPase core domain of the conserved ATPase domain located in its center21 (Fig. 1a). The founding member in Escherichia coli (EcRecQ), five RecQ N-terminal region possesses homology to the essential DNA helicases have been identified in humans: RecQ1, BLM, WRN, replication initiation factor Sld2 from Saccharomyces cerevisiae (aa RecQ4 and RecQ5. While RecQ1 and RecQ5 have not been 1–400)22,23. Accordingly, RecQ4 assumes an important function in linked to human pathogenesis, defects in BLM and WRN are the initiation of eukaryotic DNA replication22,24,25. In addition to a causative for Bloom Syndrome6 and Werner Syndrome7, nuclear targeting signal (NTS)26, a mitochondrial localization respectively. RecQ4 mutations are linked to three autosomal sequence was identified within the N-terminus27. Thus, RecQ4 is recessive diseases: Rothmund-Thomson-Syndrome (RTS) type II, the only RecQ helicase found in mitochondria as well as in the RAPADILINO Syndrome and Baller-Gerold-Syndrome cytosol and the nucleus, raising the possibility that RecQ4 is also (BGS). All three RecQ4-associated syndromes share common involved in mtDNA replication and/or maintenance28,29.Although clinical features including skeletal abnormalities (for example, the N-terminus is predicted to be largely unstructured, specific radial ray defects) and growth retardation. In addition, binding regions for RNA, Holiday-Junctions and G-quadruplex RTS type II individuals are characterized by skin abnormalities DNA have been identified throughout the entire N-terminal 430 aa (poikiloderma), symptoms of premature aging and a high risk for (refs 30–32). While the N-terminus is indispensible for viability developing osteosarcoma. While the RAPADILINO phenotype due to its implication in DNA replication initiation and typically lacks the unique RTS characteristics, these patients embryogenesis33, the DNA protective character of RecQ4 has feature an elevated risk for developing both, osteosarcoma and been assigned to its helicase domain and the unique C- lymphoma8. terminus34,35 and the vast majority of the disease-causing RecQ proteins are ATP- and DNA-dependent super family 2 mutations within RecQ4 are located in these regions8. However, (SF2) helicases and separate double stranded DNA (dsDNA) in a high-resolution structural information was so far limited to two 30 to 50 direction. Most RecQ helicases feature a set of conserved small regions within the N-terminal part of RecQ4. NMR studies domains, thereby permitting genuine helicase function, of the first 54 aa revealed a homeodomain-like DNA-interaction interactions with other proteins and, most importantly, the motif36 and more recently, a short Zn2 þ -binding motif upstream interaction with a variety of DNA-metabolism intermediate of the ATPase domain, the so-called Zn-knuckle (aa 610–634), was structures. These RecQ-characteristic domains are the ATPase characterized in Xenopus laevis RecQ4 (ref. 31). motor domain, the RecQ-C-terminal (RQC) domain and the Here we present the crystal structure of the human RecQ4 Helicase and RNase D-like C-terminal domain (HRDC; Fig. 1a). helicase, encompassing its central ATPase domain and a large The most conserved element is the ATPase core, comprising two fraction of its unique C-terminus. Downstream of the ATPase tandem RecA-like folds termed helicase domain 1 and 2 (HD1 and core, we identify a novel domain, which features homology to HD2), which feature the characteristic sequence motifs of SF2 WH domains of various prokaryotic DNA-binding proteins and helicases9. In addition, the HD1 of all RecQ helicases features a coordinates a Zn2 þ -ion, yet lacks structural resemblance to the conserved aromatic-rich sequence motif, the aromatic-rich loop conserved RQC domain. Our structural and biochemical analysis (ARL), located between helicase motifs II and III10.Thismotif provides insights into DNA substrate binding by RecQ4 and its represents a ssDNA sensor element, coupling DNA-binding to helicase mechanism and allows us to draw conclusions about the structural rearrangements in HD1, thereby indirectly enabling ATP functional relevance of RecQ4-associated diseases. hydrolysis. Less conserved, the RQC domain is located downstream of the HDs and, in concert with the ATPase domain, constitutes the functional core unit for helicase activity. The RQC domain consists Results of a Zn2 þ -binding element and a winged-helix (WH)-like domain, Overall structure. The RecQ4427-1116 model was refined to a which mediates sequence-independent contacts with the DNA and resolution of 2.75 Å (Table 1) and contains aa 449–1111 (Fig. 1b). is further involved in the oligomerization status of RecQ Two disordered regions within the C-terminus (aa 858–882 and helicases11,12. In addition, a b-hairpin element in the aa 975–983) and two short areas within the ATPase domain (aa RecQ-conserved WH domain was found to destabilize the 664–667 and aa 727–734) are not resolved. HD1 and HD2 adopt Watson–Crick base-pairing at the ssDNA/dsDNA junction and the typical RecA-like fold, which is characteristic for SF1 and SF2 thereby enables helicase function11–14. Although the WH domain is helicases9. Two ‘bridging’ a-helices (aa 823–835 and aa conserved in most RecQ proteins, the structural importance of the 1046–1079) link HD2 to a unique domain further downstream b-hairpin for dsDNA separation was demonstrated only for the (aa 836–1045), which is not present in other RecQ helicases. human RecQ helicases RecQ1 (refs 11,12), WRN13 and BLM14. One feature of this novel domain is the coordination of a Bacterial RecQ homologues contain a shorter version of the Zn2 þ -ion (Supplementary Fig. 3 and Table 1). This new domain b-hairpin, which does not interact with the bases at the (subsequently designated RecQ4-Zn2 þ -binding domain— 2 NATURE COMMUNICATIONS | 8:15907 | DOI: 10.1038/ncomms15907 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | DOI: 10.1038/ncomms15907 ARTICLE a 1 340 510 609 EcRecQ HD1 HD2 Zn WH ATPase domain RQC HRDC 163 418 592 649 HsRecQ1 HD1 HD2 Zn WH ATPase domain RQC 1 642 993 1194 1417 HsBLM HD1 HD2 Zn WH ATPase domain RQC HRDC 1 462668 819 836 1044 1208 HsRecQ4 HD1 HD2 Zn2+ Sld2 homology ATPase domain R4ZBD CTD b HD1 HD1 HD2 N N HD2 C C 90° ARL Zn2+-ion Bridging helix α11 R4ZBD Bridging helix α19 Figure 1 | Overall structure of RecQ4. (a) Comparison of the domain architecture of E. coli (Ec)RecQ and the Homo sapiens (Hs)RecQ helicases BLM, RecQ1 and RecQ4. The ATPase domain, comprising HD1 and HD2, is highly conserved among all RecQ proteins.
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