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VIEW Open Access Nanobiomotors of Archaeal DNA Repair Machineries: Current Research Status and Application Potential Wenyuan Han1,2, Yulong Shen1* and Qunxin She2*

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VIEW Open Access Nanobiomotors of Archaeal DNA Repair Machineries: Current Research Status and Application Potential Wenyuan Han1,2, Yulong Shen1* and Qunxin She2* Han et al. Cell & Bioscience 2014, 4:32 http://www.cellandbioscience.com/content/4/1/32 Cell & Bioscience REVIEW Open Access Nanobiomotors of archaeal DNA repair machineries: current research status and application potential Wenyuan Han1,2, Yulong Shen1* and Qunxin She2* Abstract Nanobiomotors perform various important functions in the cell, and they also emerge as potential vehicle for drug delivery. These proteins employ conserved ATPase domains to convert chemical energy to mechanical work and motion. Several archaeal nucleic acid nanobiomotors, such as DNA helicases that unwind double-stranded DNA molecules during DNA damage repair, have been characterized in details. XPB, XPD and Hjm are SF2 family helicases, each of which employs two ATPase domains for ATP binding and hydrolysis to drive DNA unwinding. They also carry additional specific domains for substrate binding and regulation. Another helicase, HerA, forms a hexameric ring that may act as a DNA-pumping enzyme at the end processing of double-stranded DNA breaks. Common for all these nanobiomotors is that they contain ATPase domain that adopts RecA fold structure. This structure is characteristic for RecA/RadA family proteins and has been studied in great details. Here we review the structural analyses of these archaeal nucleic acid biomotors and the molecular mechanisms of how ATP binding and hydrolysis promote the conformation change that drives mechanical motion. The application potential of archaeal nanobiomotors in drug delivery has been discussed. Keywords: Archaea, Nanobiomotor, Helicase, RecA fold, DNA repair Introduction potential in the biotechnological application. Nanobio- Biomolecules exhibit good potential in nanomedicine motors convert chemical energy into mechanical work since they can be used to deliver new potential drugs and motion, a reaction essential for many cellular pro- such as short interference RNAs (siRNAs). Currently, cesses in living organisms, and they are widespread in lipid nanoparticles represent the most advanced biomo- every living organism on Earth regardless whether they lecular system for delivering siRNAs with which thera- belong to Bacteria, Archaea or Eukarya, collectively as the peutic effects have been observed [1]. However, the three domains of life. Organisms of the two former do- usefulness of this type of nanoparticle is compromised mains comprise of single cellular prokaryotes that often by the finding that multiple cellular signaling effectors co-inhabit in environments whereas the latter includes are required for initial cellular entry of lipid nanoparticle higher eukaryotes such as human beings. Being prokary- during which the internalized siRNAs have undergone otic, Archaea and Bacteria share some traits such as lack- exocytosis [2]. Conceivably, it is very important to inves- ing any distinct nuclear membrane to separate their tigate other biomolecules for their potential in safe and genetic materials from the cytoplasm and utilizing similar effective drug delivery. metabolic pathways. However, Archaea is only distantly Biomolecular motors (nanobiomotors) belong to an in- related to Bacteria phylogenetically [3]. This is reflected by teresting class of biomolecules that exhibit a good the conservation of information-processing machineries in Archaea and Eukarya, including molecular machineries of chromosome replication, DNA damage repair, gene * Correspondence: [email protected]; [email protected] 1State Key Laboratory of Microbial Technology, Shandong University, Jinan, transcription and protein translation [4,5]. People's Republic of China Specifically, many archaeal DNA repair proteins have 2Archaeal Centre, Department of Biology, University of Copenhagen, homologs in eukaryotes, including those involved in base Copenhagen Biocenter, Copenhagen, Denmark © 2014 Han et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Han et al. Cell & Bioscience 2014, 4:32 Page 2 of 12 http://www.cellandbioscience.com/content/4/1/32 excision repair (BER), nucleotide excision repair (NER) A common task in NER and HRR is that the machin- and homologous DNA recombination-mediated DNA re- eries need to open up double stranded DNA (dsDNA) at pair (HRR) [4,6,7]. BER proteins are well conserved in all the very first step. As dsDNA has a very stable structure, three domains of life and exhibit similar structures, but ar- nature has invented nucleic acid nanobiomotors, namely chaeal BER proteins still show higher sequence similarities DNA helicases to do the job, and the process is powered to the eukaryotic corresponding enzymes than to their by ATP hydrolysis. In addition to helicase motors, RecA bacterial counterparts. For the two general DNA repair family recombinases catalyze the strand exchange reac- pathways NER and HRR, archaeal and eukaryal proteins tion in homologous recombination, representing another involved in, or implicated in, the processes, are of the class of well-characterized nanobiomotors. This review same type, whereas the bacterial counterparts typically be- will summarize the biochemical and structural analyses long to another category. of the archaeal recombinases and helicases and their Only some of the eukaryal NER proteins have a homo- possible modes of action and discuss their possible ap- log in Archaea, including XPB and XPD helicases and, plication as nanomaterials. XPF and XPG/Fen-1 nucleases, because archaea also en- code several lineage-specific NER proteins. For example, DNA repair helicases are nanobiomotors driven some archaeal XPBs interact with another archaea-specific by ATP binding and hydrolysis nuclease Bax1, which is thought to be a functional homo- Helicases are ATPases that unwind DNA or RNA du- log of eukaryal XPG nuclease. The archaeal XPG/Fen-1, plex. These molecular motors convert energy from ATP on the other hand, is shown to be an essential enzyme im- hydrolysis to motion that unwinds nucleic acids. Heli- plicated in the maturation of Okazaki fragments during cases fall into six superfamilies: The SF3 to SF6 family chromosome replication [8]. Further, functional studies of helicases form a ring structure, while SF1 and SF2 family archaeal NER enzymes have revealed interesting differ- helicases function as monomers [24]. Three known ences between archaeal and eukaryal XPB and XPD pro- DNA repair helicases in Archaea fall into the SF2 family, teins. Whereas archaeal enzymes are dispensable for cell including NER helicases XPB, XPD and RecQ-like heli- viability, their eukaryal counterparts have essential func- case Hjm. These archaeal helicases contain two conserved tions in gene transcription by RNA polymerase II [9-11]. ATPase domains each of which binds ATP, promoting Homologous recombination proteins conserved in Ar- conformational changes upon ATP hydrolysis. Other chaea and Eukarya include Rad50/Mre11 (MR) complex domains are not conserved in different types of SF2 and the RadA/Rad51 recombinase. The former, together enzymes and function in substrate binding and/or in with some lineage-specific helicases and nucleases, is re- regulating the helicase activity. Crystal structures are sponsible for processing double-stranded DNA (dsDNA) available for representatives of all three types of archaeal ends into 3’-pertruding ends [12] to which the latter SF2 helicases [25-27]. binds and mediates the strand invasion reaction in hom- The discovery that components of archaeal NER ma- ologous recombination. Eukaryotic-specific helicases and chinery are homologous to eukaryotic NER proteins has nucleases involved in the processing of DNA ends in- greatly facilitated the research of archaeal/eukaryotic NER clude Sgs1 and Sae2, Exo1 in yeasts [13] and BLM and enzymes, namely the NER helicases and nucleases. To Dna2, Exo1 in humans [14], whereas archaeal-specific date, several archaeal enzymes are well characterized in- counterparts are nuclease NurA and helicase HerA [12]. cluding XPB, XPD, XPF and XPG/Fen1 as well as a few Moreover, archaea and eukaryotes encode RadA/Rad51 archaea-specific nucleases. The obtained results are incor- paralogs, such as Rad55/57 in yeast, Rad51B/C/D, Xrcc2 porated into a model accounting for the putative archaeal and Xrcc3 in mammals, and RadB, RadC in Archaea, NER process [28]: (1) the recognition of the damaged which facilitate homologous recombination by interact- DNA by the single-stranded DNA binding protein (SSB), ing with RadA/Rad51 recombinases [15-17]. (2) SSB recruits other repair proteins to the damaged site After strand invasion, DNA synthesis at the heterodu- via the C-terminal tail, (3) a helicase-nuclease complex plex region and subsequent ligation yield a Holliday formed by XPB and its partner Bax1 (bind to archaeal junction intermediate, which needs to be resolved by a XPB) is recruited to one side of the damaged DNA joint action of helicase and nuclease at a late stage of the whereas XPD and XPF may work at the other side. DNA homologous recombination pathway [18,19]. RecQ-like damage recognition could also occur via archaeal XPB enzymes, including eukaryotic helicases WRN and BLM, proteins since these proteins
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