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(MAR/SAR) Sequence: Its Vital Role in Mediating Chromosome Breakages

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(MAR/SAR) Sequence: Its Vital Role in Mediating Chromosome Breakages Tan et al. BMC Molecular Biol (2018) 19:15 https://doi.org/10.1186/s12867-018-0116-5 BMC Molecular Biology RESEARCH ARTICLE Open Access Matrix association region/scafold attachment region (MAR/SAR) sequence: its vital role in mediating chromosome breakages in nasopharyngeal epithelial cells via oxidative stress‑induced apoptosis Sang‑Nee Tan1, Sai‑Peng Sim1* and Alan S. B. Khoo2 Abstract Background: Oxidative stress is known to be involved in most of the aetiological factors of nasopharyngeal car‑ cinoma (NPC). Cells that are under oxidative stress may undergo apoptosis. We have previously demonstrated that oxidative stress-induced apoptosis could be a potential mechanism mediating chromosome breakages in naso‑ pharyngeal epithelial cells. Additionally, caspase-activated DNase (CAD) may be the vital player in mediating the chro‑ mosomal breakages during oxidative stress-induced apoptosis. Chromosomal breakage occurs during apoptosis and chromosome rearrangement. Chromosomal breakages tend to cluster in certain regions, such as matrix association region/scafold attachment region (MAR/SAR). We hypothesised that oxidative stress-induced apoptosis may result in chromosome breaks preferentially at the MAR/SAR sites. The AF9 gene at 9p22 was targeted in this study because 9p22 is a deletion site commonly found in NPC. Results: By using MAR/SAR recognition signature (MRS), potential MAR/SAR sites were predicted in the AF9 gene. The predicted MAR/SAR sites precisely match to the experimentally determined MAR/SARs. Hydrogen peroxide ­(H2O2) was used to induce apoptosis in normal nasopharyngeal epithelial cells (NP69) and NPC cells (HK1). Nested inverse polymerase chain reaction was employed to identify the AF9 gene cleavages. In the SAR region, the gene cleavage frequency of ­H2O2-treated cells was signifcantly higher than that of the non-treated cells. A few chromosomal break‑ ages were detected within the AF9 region which was previously found to be involved in the mixed lineage leukae‑ mia (MLL)-AF9 translocation in an acute lymphoblastic leukaemia patient. As for the non-SAR region, no signifcant diference in the gene cleavage frequency was found between the untreated control and H­ 2O2-treated cells. Further‑ more, ­H2O2-induced cleavages within the SAR region were reduced by caspase-3 inhibitor, which indirectly inhibits CAD. Conclusions: These results reafrm our previous fndings that oxidative stress-induced apoptosis could be one of the potential mechanisms underlying chromosome breakages in nasopharyngeal epithelial cells. MAR/SAR may play a vital role in defning the location of chromosomal breakages mediated by oxidative stress-induced apoptosis, where CAD is the major nuclease. Keywords: NPC, Oxidative stress, H2O2, Apoptosis, MAR/SAR, AF9 gene *Correspondence: [email protected] 1 Department of Paraclinical Sciences, Faculty of Medicine and Health Sciences, Universiti Malaysia Sarawak, Kota Samarahan, Sarawak, Malaysia Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/ publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Tan et al. BMC Molecular Biol (2018) 19:15 Page 2 of 21 Background place at the base of the DNA loop [30, 31]. We hypoth- Nasopharyngeal carcinoma (NPC) is a type of malignant esised that H2O2-induced apoptosis may cause chromo- solid tumour which has been associated with multiple somal breakages at MAR/SAR resulting in chromosome factors. One of the strong risk factors of NPC is Epstein– rearrangement in nasopharyngeal epithelial cells. Barr virus (EBV) infection [1, 2]. A previous study has Tis study focuses on the AF9 gene which is located at reported increased levels of immunoglobulin G (IgG) and 9p22 because 9p22 is one of the deletion hotspots in NPC immunoglobulin A (IgA) antibodies to EBV viral capsid [32]. Te AF9 gene is 280,880 bp in length. Te nucleo- antigen (VCA) and early antigen (EA) in NPC patients tide position of its exons and introns are shown in Addi- [1]. Besides, a case–control study of NPC among Malay- tional fle 1. Strissel et al. have identifed two MAR/SARs sian Chinese has reported that salted fsh consumption within the AF9 gene. Tese two MAR/SARs were desig- during childhood was a signifcant risk factor for devel- nated as SAR1 and SAR2 [28]. oping NPC [3]. Mutagenic activity has been detected in In the present study, in silico prediction of MAR/SAR the urine collected from experimental rats that were reg- sites was performed in the AF9 gene. It was found that ularly fed with salted fsh [4]. In addition, Chinese salted in the region that contains MAR/SAR (SAR region), the fsh was found to cause nasal cavity tumours in rats [5, gene cleavage frequency of H2O2-treated cells was higher 6]. Tese fndings suggested the presence of carcinogenic than that of the untreated control. On the contrary, in substances in salted fsh. Most studies pointed toward the region that does not contain MAR/SAR (non-SAR nitrosamines and nitrosamine precursors, which have region), there was no signifcant diference in gene cleav- been recognised as animal carcinogens [7, 8]. In addition, age frequency between untreated and H 2O2-treated cells. long-term exposures to intense industrial heat, formal- Tese observations are true for both normal nasopharyn- dehyde, cigarette smoke and wood dust have also been geal epithelial and NPC cells. Moreover, the oxidative found to be signifcantly associated with NPC [3, 9–12]. stress-induced chromosome breakages within the SAR Recently, chronic infammation of sinonasal tract has region were reduced by caspase-3 inhibitor, which indi- been increasingly recognised as a risk factor for NPC [13, rectly inhibits CAD. Our results suggested that MAR/ 14]. SAR may play an important role in defning the location It is important to note that, all of these aetiological of chromosome breaks mediated by oxidative stress- factors provoke the production of reactive oxygen spe- induced apoptosis, where CAD is the essential nuclease. cies (ROS) [15–20]. Additionally, ROS was found to be Tese chromosomal breakages may in turn lead to chro- involved in EBV reactivation in NPC cells after treatment mosome aberrations in nasopharyngeal epithelial cells. with N-methyl-N′-nitro-N-nitroguanidine (MNNG) [21]. Te ROS-mediated EBV reactivation was inhibited by Methods apigenin which has been suggested to be a potent ROS Cell lines and chemicals scavenger [22]. Increased ROS may cause DNA double- NP69 normal nasopharyngeal epithelial cell line and strand breaks and error-prone repair. Tis may in turn HK1 NPC cell line were kindly provided by Prof. Tsao Sai lead to genomic instability [23]. Te cancer cells and Wah (Te University of Hong Kong, Hong Kong, China) infammatory cells in stroma of NPC patients have been and Prof. Lo Kwok Wai (Te Chinese University of Hong found to contain oxidative and nitrative DNA lesions Kong, Hong Kong, China). StemPro ACC UTA SE Cell [24]. Oxidative stress may trigger apoptosis, a process of Dissociation Reagent, Keratinocyte-SFM medium, RPMI programmed cell death [25]. We have previously demon- 1640 medium, penicillin, streptomycin, l-glutamine and strated that oxidative stress-induced apoptosis resulted in fetal bovine serum were purchased from GIBCO, Invit- chromosomal breakages in normal nasopharyngeal epi- rogen, USA. Camptothecin (CPT) was purchased from thelial and NPC cells. In addition, the apoptotic nuclease, Santa Cruz Biotechnology, California, USA. Hydrogen caspase-activated DNase (CAD) may be a major player in peroxide (H2O2) was bought from MP Biomedicals, USA. mediating these chromosomal breakages [26]. Annexin V-Fluorescein isothiocyanate (FITC) Apopto- Chromosomal breakage is an early event in both apop- sis Detection Kit I (BD Pharmingen™) and Flow Cytom- totic DNA fragmentation and chromosome rearrange- etry Mitochondrial Membrane Potential Detection Kit ment. Previous studies revealed that chromosome breaks (BD™MitoScreen) were obtained from Becton–Dickin- tend to fall within certain regions which contain specifc son Biosciences, USA. Caspase-Glo 3/7 Assay Kit and chromatin structural elements, such as the matrix attach- dNTP mix were purchased from Promega, USA. Cas- ment region/scafold attachment region (MAR/SAR) [27, pase-3 inhibitor II (Z-DEVD-FMK) was obtained from 28]. MAR/SAR is the DNA sequence where the DNA Calbiochem, USA. Isoamyl alchohol was procured from loop structure binds to nuclear scafold/matrix proteins Fluka, Switzerland. Sodium dodecyl sulfate (SDS) and [29]. In the early stage of apoptosis, DNA cleavages take phenol were bought from Amresco, USA. Ammonium Tan et al. BMC Molecular Biol (2018) 19:15 Page 3 of 21 acetate was from Merck, Germany. Chloroform was Extract (BPE), 100 U/ml penicillin, 100 µg/ml streptomy- obtained from R&M Chemicals, UK. All the restriction cin and 2% (v/v) heat-inactivated fetal bovine serum. HK1 enzymes, T4 DNA Ligase and DNA Polymerase I Large cells were cultured in RPMI 1640 medium supplemented (Klenow) Fragment were purchased from New England with 2 mM l-glutamine, 100 U/ml penicillin, 100 µg/ml Biolabs (NEB), USA. QIAquick Gel Extraction Kit and streptomycin and 10% (v/v) heat-inactivated fetal bovine QIAquick Nucleotide Removal Kit were obtained from serum. Cells were incubated at 37 °C with 5% CO2. QIAGEN, Germany. Phusion High-Fidelity DNA Poly- merase was obtained from Finnzymes, Finland. PCR Detection of phosphatidylserine (PS) externalisation 5 primers were bought from First Base Laboratories. NP69 cells (1.5 × 10 ) were plated in 150 mm culture dishes and allowed to grow for 48 h.
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