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Understanding Molecular Functions of the SMC5/6 Complex

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G C A T T A C G G C A T genes Review Scaffolding for Repair: Understanding Molecular Functions of the SMC5/6 Complex Mariana Diaz 1,2 and Ales Pecinka 1,* ID 1 Institute of Experimental Botany of the Czech Academy of Sciences (IEB), Centre of the Region Haná for Biotechnological and Agricultural Research, Šlechtitelu˚ 31, 77900 Olomouc-Holice, Czech Republic 2 Max Planck Institute for Plant Breeding Research (MPIPZ), Carl-von-Linné-Weg 10, 50829 Cologne, Germany; [email protected] * Correspondence: [email protected]; Tel.: +420-585-238-709 Received: 15 November 2017; Accepted: 4 January 2018; Published: 12 January 2018 Abstract: Chromosome organization, dynamics and stability are required for successful passage through cellular generations and transmission of genetic information to offspring. The key components involved are Structural maintenance of chromosomes (SMC) complexes. Cohesin complex ensures proper chromatid alignment, condensin complex chromosome condensation and the SMC5/6 complex is specialized in the maintenance of genome stability. Here we summarize recent knowledge on the composition and molecular functions of SMC5/6 complex. SMC5/6 complex was originally identified based on the sensitivity of its mutants to genotoxic stress but there is increasing number of studies demonstrating its roles in the control of DNA replication, sister chromatid resolution and genomic location-dependent promotion or suppression of homologous recombination. Some of these functions appear to be due to a very dynamic interaction with cohesin or other repair complexes. Studies in Arabidopsis indicate that, besides its canonical function in repair of damaged DNA, the SMC5/6 complex plays important roles in regulating plant development, abiotic stress responses, suppression of autoimmune responses and sexual reproduction. Keywords: SMC5/6; genome stability; DNA damage repair; Structural maintenance of chromosomes; chromatin; chromosomes 1. Introduction The eukaryotic nuclear genome is organized into linear chromosomes. Chromosomal DNA is wrapped around histone octamers forming nucleosomes. Nucleosomes are the primary chromatin units, which are folded into chromatin fibers and the fibers into domains of different density and accessibility [1,2]. Chromosome and chromatin stability is challenged by endogenous factors including free radicals, replication errors and topological stress [3]. Exogenous damage is exerted by adverse environmental conditions such as UV radiation, oxidative stress and chemical pollutants [4]. These (and other) factors challenge genome stability by a wide range of toxic effects including base oxidation, alkylation, DNA single and double strand breaks (SSBs and DSBs) and formation of non-native bonds within and/or between DNA strands [5]. Unrepaired or misrepaired lesions result in mutations, which compromise gene functionality, cause loss/gain of genetic information and induce chromosome instability. This problem may be particularly pronounced in obligatory phototrophic sessile organisms such as plants, which are exposed to challenging environmental conditions without possibility for escape [6,7]. Structural maintenance of chromosomes (SMC) complexes are the key regulators of chromosome dynamics, structure and function in eukaryotes (reviewed in [8–12]). They operate from the scale of whole chromosomes in chromosome segregation to few base pairs in DNA damage repair. The core subunits of SMC complexes are SMC proteins, which are large polypeptides (1000–1300 amino acids) Genes 2018, 9, 36; doi:10.3390/genes9010036 www.mdpi.com/journal/genes Genes 2018, 9, 36 2 of 16 Genes 2018, 9, 36 2 of 16 The core subunits of SMC complexes are SMC proteins, which are large polypeptides (1000–1300 amino acids) containing Walker A and Walker B motifs at their N- and C-terminal globular domains. containingThe primary Walker step towards A and Walker functional B motifs SMC at protein their N- is and folding C-terminal at the hinge globular domain domains. and coiling The primary of the steparms. towards This brings functional the C- SMC and proteinN-terminal is folding globular at the domains hinge domain together and and coiling constitutes of the arms.heads This with brings ATP- thedependent C- and N-terminalDNA binding globular activity domains [13]. The together most ch andaracterized constitutes SMC heads complex with ATP-dependentis cohesin (containing DNA bindingSMC1 and activity SMC3). [13 ].It Thecontrols most dynamics characterized of sister SMC chromatid complex is cohesion cohesin (containingand thus affects SMC1 chromosome and SMC3). Itsegregation, controls dynamics meiotic of recombination sister chromatid and cohesion DNA anddamage thus repair affects chromosome(reviewed in segregation,[9–11]). Condensin meiotic recombinationcomplex (containing and DNA SMC2 damage and SMC4) repair plays (reviewed a pivota inl [ 9role–11 ]).in chromosome Condensin complex folding (containing and condensation SMC2 andduring SMC4) interphase plays aand pivotal nuclear role division. in chromosome Finally, foldingthe third and complex condensation consisting during of SMC5 interphase and SMC6 and nuclearheterodimer division. backbone, Finally, called the third SMC5/6, complex is famous consisting for its of role SMC5 in andmaintaining SMC6 heterodimer genome stability backbone, [8]). calledBeside SMC5/6, the SMC5 is famous and SMC6, for its rolethis incomplex maintaining contains genome six stabilityadditional [8]). N BesideON-SMC the E SMC5LEMENT and SMC6,(NSE) thissubunits complex (Figure contains 1A,B; six Table additional 1) and the NON-SMC whole comp ELEMENTlex is organized (NSE) subunits into three (Figure sub-complexes:1A,B and Table NSE2-1) andSMC5-SMC6, the whole complexNSE1-NSE3-NSE4 is organized and into NSE5-NSE6 three sub-complexes: acting as specialized NSE2-SMC5-SMC6, functional NSE1-NSE3-NSE4 modules [14–16]. andIn spite NSE5-NSE6 of increasing acting number as specialized of studies, functional the functions modules of [ 14SMC5/6–16]. In complex spite of increasingstill remain number relatively of studies,poorly understood. the functions To of foster SMC5/6 this research, complex we still pr remainovide an relatively overview poorly on the understood. current understanding To foster this of research,SMC5/6 complex we provide functions. an overview on the current understanding of SMC5/6 complex functions. Figure 1. Structural maintenance of chromosomes (SMC) 5/6 complex composition and functions. (A) Figure 1. Structural maintenance of chromosomes (SMC) 5/6 complex composition and functions. Consensual model of SMC5/6 complex without and (B) with species-specific positions of NON-SMC (A) Consensual model of SMC5/6 complex without and (B) with species-specific positions ofELEMENT NON-SMC (NSE) ELEMENT 5(-like) (NSE)and NSE6(-like) 5(-like) and subunits NSE6(-like) in Schizosaccharomyces subunits in Schizosaccharomyces pombe, Saccharomyces pombe, Saccharomycescerevisiae, Arabidopsis cerevisiae thaliana, Arabidopsis and thalianaHomo sapiensand Homo. (C) sapiensHypothetical.(C) Hypothetical function of function NSE5-NSE6 of NSE5-NSE6 dimer in dimermultimerizing in multimerizing SMC5/6 SMC5/6complexes complexes via their via theirheads heads (top) (top) or orhinges hinges (bottom). (bottom). ( (DD)) ReplicationReplication intermediateintermediate structurestructure bypassingbypassing DNADNA damagedamage sitesite (red(red square).square). ((EE)) TopologicalTopological stressstress occurringoccurring duringduring DNADNA replicationreplication andand atat replicationreplication forkfork barriersbarriers (RFBs)(RFBs) representedrepresented byby thethe positivepositive supercoilsupercoil (+SC)(+SC) aheadahead ofof thethe replicationreplication forkfork andand sistersister chromatidchromatid intertwiningintertwining (SCIs)(SCIs) betweenbetween thethe nascentnascent chromatids.chromatids. ((FF)) RoleRole ofof SMC5/6SMC5/6 complex inin telomeretelomere lengthlength maintenance.maintenance. ((GG)) SpeculativeSpeculative modelmodel forfor SUMOylationSUMOylation ofof transcriptionaltranscriptional modulations modulations by by SMC5/6 SMC5/6 complex.complex. NoteNote thatthat thethe position position of of SMC5/6 SMC5/6 complexcomplex inin imagesimages ((CC),), ((EE),), ((FF)) andand ((GG)) isis onlyonly speculative.speculative. Genes 2018, 9, x; doi: FOR PEER REVIEW www.mdpi.com/journal/genes Genes 2018, 9, 36 3 of 16 Table 1. Overview of Structural maintenance of chromosomes (SMC) complex 5/6 subunits in budding yeast (Saccharomyces cerevisiae), fission yeast (Schizosaccharomyces pombe), fruit fly (Drosophila melanogaster), human (Homo sapiens) and Arabidopsis (Arabidopsis thaliana). NA-information not available. S. cerevisiae S. pombe D. megalonaster H. sapiens A. thaliana SMC5 SMC5/SPR18 SMC5 SMC5 SMC5 SMC6/RHC18 SMC6/RAD18 SMC6/JNJ SMC6 SMC6A, SMC6B/MIM NSE4/QRI2 NSE4/RAD62 NSE4 NSE4A, NSE4B NSE4A, NSE4B NSE1 NSE1 NSE1 NSE1 NSE1 NSE3 NSE3 NSE3/MAGE NSE3/MAGE-G1 NSE3 NSE2/MMS21 NSE2/PLI2 QUIJOTE/CERVANTE NSE2/MMS21 NSE2/MMS21/HPY2 NSE5/YML023c NSE5 NA SLF1 SNI1 KRE29 NSE6 NA SLF2 ASAP1 2. Architecture of SMC5/6 Complex 2.1. NSE1-NSE3-NSE4 Subcomplex NSE1-NSE3-NSE4 trimer is a highly conserved part of the SMC5/6 complex responsible for binding DNA and bridging SMC heads. NSE1 contains a RING-like domain necessary for the NSE1-NSE3-NSE4 trimer formation and recruitment of NSE4 and SMC5 to the sites of DNA damage [17–20]. Mutations in the RING-like domain lead to DNA damage hypersensitivity and full deletion of NSE1 is lethal in Saccharomyces
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