A Structural Perspective on the Regulation of Human Single-Stranded DNA Binding Protein 1 (Hssb1, OBFC2B) Function in DNA Repair
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Computational and Structural Biotechnology Journal 17 (2019) 441–446 Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/csbj Mini Review A Structural Perspective on the Regulation of Human Single-Stranded DNA Binding Protein 1 (hSSB1, OBFC2B) Function in DNA Repair Teegan Lawson a,1, Serene El-Kamand a,1, Ruvini Kariawasam a,1, Derek J. Richard c,⁎⁎, Liza Cubeddu a,b,⁎, Roland Gamsjaeger a,b,⁎ a School of Science and Health, Western Sydney University, Sydney, Locked Bag 1797, Penrith, NSW 2751, Australia b School of Life and Environmental Sciences, University of Sydney, NSW 2006, Australia c Genome Stability Laboratory, Cancer and Ageing Research Program, Institute of Health and Biomedical Innovation, Translational Research Institute, Queensland University of Technology, Woolloongabba, Queensland 4102, Australia article info abstract Article history: Single-stranded DNA binding (SSB) proteins are essential to protect singe-stranded DNA (ssDNA) that exists as a Received 27 February 2019 result of several important DNA repair pathways in living cells. In humans, besides the well-characterised Repli- Received in revised form 25 March 2019 cation Protein A (RPA) we have described another SSB termed human SSB1 (hSSB1, OBFC2B) and have shown Accepted 26 March 2019 that this protein is an important player in the maintenance of the genome. In this review we define the structural Available online 28 March 2019 and biophysical details of how hSSB1 interacts with both DNA and other essential proteins. While the presence of Keywords: the oligonucleotide/oligosaccharide (OB) domain ensures ssDNA binding by hSSB1, it has also been shown to fi hSSB1 self-oligomerise as well as interact with and being modi ed by several proteins highlighting the versatility OBFC2B that hSSB1 displays in the context of DNA repair. A detailed structural understanding of these processes will likely SSBs lead to the designs of tailored hSSB1 inhibitors as anti-cancer drugs in the near future. DNA repair © 2019 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural NMR Biotechnology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). OB domains Contents 1. Introduction.............................................................. 441 2. DNABindingofhSSB1.......................................................... 442 3. Self-OligomerisationofhSSB1...................................................... 443 4. Post-Translation ModificationsofhSSB1................................................. 444 5. hSSB1BindingtoOtherProteinsandMolecules.............................................. 445 6. ConcludingRemarks.......................................................... 445 Acknowledgement.............................................................. 445 References................................................................. 445 1. Introduction threat from both endogenous and exogenous factors, with each cell experiencing tens of thousands of damage events each day [1–3]. This Damage to the genetic code must be repaired quickly and efficiently damage must be repaired with high fidelity for the preservation of the in order to prevent genomic instability. Cellular DNA is under constant genetic and epigenetic code. Failure to protect the DNA can results in ⁎ Correspondence to: Liza Cubeddu and Roland Gamsjaeger, School of Science and Health, Western Sydney University, Sydney, Locked Bag 1797, Penrith, NSW 2751, Australia. ⁎⁎ Correspondence to: Derek J. Richard, Genome Stability Laboratory, Cancer and Ageing Research Program, Institute of Health and Biomedical Innovation, Translational Research Institute, Queensland University of Technology, Woolloongabba, Queensland 4102, Australia. E-mail addresses: [email protected] (T. Lawson), [email protected] (S. El-Kamand), [email protected] (R. Kariawasam), [email protected] (D.J. Richard), [email protected] (L. Cubeddu), [email protected] (R. Gamsjaeger). 1 Contributed equally. https://doi.org/10.1016/j.csbj.2019.03.014 2001-0370/© 2019 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 442 T. Lawson et al. / Computational and Structural Biotechnology Journal 17 (2019) 441–446 the loss or alteration of gene sequences, which in turn can alter protein 2. DNA Binding of hSSB1 structure, function and expression; potentially leading to disease states such as cancer and neurodegenerative disorders [4,5]. To protect the ge- As mentioned above, the most common feature among SSB proteins netic code cells have evolved efficient DNA repair pathways that can de- is the OB domain that binds DNA, RNA, and proteins [22–24](Fig. 1, tect, signal and repair the genome. There are five primary repair blue). While the sequence varies significantly between OB folds from pathways, Mismatch repair (MMR), Base Excision Repair Pathway different organisms, these domains share several important structural (BER), Nucleotide Excision Repair Pathway, Homologous Recombina- features [25]: The core is made up of five anti-parallel β-strands tion Pathway and Non-homologous End-joining Pathway. Each repair organised into a β-barrel structure and a ssDNA binding cleft is formed pathway specialises in a particular form of DNA damage, although on one end of the β-barrel whereas the other end is capped by an α- there is a degree of substrate overlap [6–8]. helix (Fig. 1). The length and amino acid sequence of the connecting One common element of DNA damage and repair is the presence of loops between the β-strands is responsible for the differences in DNA single-stranded DNA (ssDNA) which occurs during the processing by binding specificities of OB domains from different SSBs [25]. repair proteins. This ssDNA is vulnerable to further damage or digestion The domain organisations of SSBs from several species has been ex- by nucleases and must therefore be protected. Early in evolutionary life tensively studied over the years. For example, the SSB from Escherichia a family of proteins evolved that bind to and protect ssDNA. The single- coli (EcoSSB) exhibits a ‘simple’ domain organisation (one sole DNA stranded DNA binding (SSB) protein family (which is characterised by binding OB domain) that utilises its OB domains to oligomerise into a the presence of a highly structurally conserved oligonucleotide/oligo- functional homotetramer [26–29]. In contrast, RPA displays a ‘complex’ saccharide binding OB domain) is present in all life forms and is domain organisation in which six OB domains spanning across three encoded by many viruses indicating the importance of this protein subunits (RPA70, RPA32 and RPA14) are arranged into a heterotrimer (reviewed in [9–12]). [30–33]. Notably, RPA also engages multiple OB domains for DNA bind- It was initially thought that humans only had a heterotrimeric Rep- ing, resulting in a significant higher overall affinity compared to hSSB1 lication Protein A (RPA) family member composed of RPA70, RPA32 and (nM versus μM) [34,35]. RPA14 [13] and the mitochondrial SSB (mtSSB) encoded within the ge- hSSB1 is a ‘simple’ SSB and exhibits a monomeric state under re- nome. However, we have described two other functional members of ducing conditions [12,14,36] in analogy to its archaeal ancestor the SSB subfamily in humans [14]. While hSSB1 appears to be ubiqui- Sulfolobus solfataricus (SsoSSB) that is structurally highly similar to tously expressed in all tissues, hSSB2 expression seems to be restricted hSSB1 [37,38]. However, under oxidised conditions, hSSB1 can self- predominantly to immune cells and the testes. hSSB1 has been demon- oligomerise into homotetramers, which has functional implications strated to be involved in the repair of double strand DNA breaks, stalled in the repair of oxidative DNA damage [17,39,40] (for details see DNA replication forks and oxidised DNA adducts [14–20]. While the role Section 3). of hSSB2 is not yet clear, it appears to functionally compensate for a loss Ren et al. have recently solved the structure of the sensor of ssDNA of hSSB1 in several pathways [21]. (SOSS1) complex (composed of hSSB1, INTS3 and C9ORF80) using X- Most published studies focus on the ssDNA binding ability of hSSB1 ray crystallography methods, shedding light on how the hSSB1 OB (Section 2), however, more recently, hSSB1 has also been shown to be domain binds ssDNA [41]. The crystal structure revealed the structural self-oligomerise in the context of oxidative DNA damage repair features of the OB domain: residues 5–109 make up the OB fold with (Section 3). In addition, both the OB domain and the flexible carboxyl- five β-strands (β1, β3, β4, β5 and β6) organised into a β-barrel, and a terminal (C-terminal) tail have been revealed to interact with other im- small α-helix (α1) situated between β3andβ4. An additional small portant proteins implicated in the maintenance of the genome (Sections β-strand (β2) is located anti-parallel to β3[41](Fig. 1). Importantly, 4 and 5). Fig. 1 depicts the structure of hSSB1 and summarises all pro- residues 110–211 form an unstructured C-terminal tail [41]thatisun- tein, PAR and DNA binding interfaces discussed in this review. able to interact with ssDNA [14]. In contrast, the C-terminal tail of EcoSSB has been shown to play an active role in regulating