Publications by authors named "Shazrul Fazry"

15 Publications

  • Page 1 of 1

Sago starch nanocrystal-stabilized Pickering emulsions: Stability and rheological behavior.

Int J Biol Macromol 2021 Mar 24. Epub 2021 Mar 24.

Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor Darul Ehsan, Malaysia. Electronic address:

This study presents the isolation of SNC from sago starch and its performance as proficient particle emulsifier. It highlights the impact of SNC on the stability and rheological properties of oil-in-water (o/w) emulsions. The percentage yield of the SNC obtained was equivalent to 25 ± 0.1% (w/w) with particle diameters ranging from 25 to 100 nm. A series of Pickering emulsion at different ratios of oil (5%-35% v/v) and SNC (1%-4% w/v) was prepared for further investigations. The mean droplet diameter of emulsions obtained was ranged from 19.12 to 35.96 μm, confirming the effects of both SNC and oil content on the droplet's diameter distribution. Formulations with 4.0 wt% of SNC exhibited the maximum stability against coalescence. Results obtained have justified that the SNC can be used as an alternative solid emulsifier in producing stable emulsion with desired properties for various applications.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.03.132DOI Listing
March 2021

Mutated Shiitake extracts inhibit melanin-producing neural crest-derived cells in zebrafish embryo.

Comp Biochem Physiol C Toxicol Pharmacol 2021 Mar 15;245:109033. Epub 2021 Mar 15.

Department of Food Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia; Tasik Chini Research Centre, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia; Innovative Centre for Confectionery Technology (MANIS), Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia. Electronic address:

The ability of natural extracts to inhibit melanocyte activity is of great interest to researchers. This study evaluates and explores the ability of mutated Shiitake (A37) and wildtype Shiitake (WE) extract to inhibit this activity. Several properties such as total phenolic (TPC) and total flavonoid content (TFC), antioxidant activity, effect on cell and component profiling were conducted. While having no significant differences in total phenolic content, mutation resulted in A37 having a TFC content (1.04 ± 0.7 mg/100 ml) compared to WE (0.86 ± 0.9 mg/100 ml). Despite that, A37 extract has lower antioxidant activity (EC50, A37 = 549.6 ± 2.70 μg/ml) than WE (EC50 = 52.8 ± 1.19 μg/ml). Toxicity tests on zebrafish embryos show that both extracts, stop the embryogenesis process when the concentration used exceeds 900 μg/ml. Although both extracts showed pigmentation reduction in zebrafish embryos, A37 extract showed no effect on embryo heartbeat. Cell cycle studies revealed that WE significantly affect the cell cycle while A37 not. Further tests found that these extracts inhibit the phosphorylation of Glycogen synthase kinase 3 β (pGSK3β) in HS27 cell line, which may explain the activation of apoptosis in melanin-producing cells. It was found that from 19 known compounds, 14 compounds were present in both WE and A37 extracts. Interestingly, the presence of decitabine in A37 extract makes it very potential for use in the medical application such as treatment of melanoma, skin therapy and even cancer.
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http://dx.doi.org/10.1016/j.cbpc.2021.109033DOI Listing
March 2021

Comprehensive computational target fishing approach to identify Xanthorrhizol putative targets.

Sci Rep 2021 Jan 15;11(1):1594. Epub 2021 Jan 15.

Department of Food Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600, Bangi, Selangor, Malaysia.

Xanthorrhizol (XNT), is a bioactive compound found in Curcuma xanthorrhiza Roxb. This study aimed to determine the potential targets of the XNT via computational target fishing method. This compound obeyed Lipinski's and Veber's rules where it has a molecular weight (MW) of 218.37 gmol, TPSA of 20.23, rotatable bonds (RBN) of 4, hydrogen acceptor and donor ability is 1 respectively. Besides, it also has half-life (HL) values 3.5 h, drug-likeness (DL) value of 0.07, oral bioavailability (OB) of 32.10, and blood-brain barrier permeability (BBB) value of 1.64 indicating its potential as therapeutic drug. Further, 20 potential targets were screened out through PharmMapper and DRAR-CPI servers. Co-expression results derived from GeneMANIA revealed that these targets made connection with a total of 40 genes and have 744 different links. Four genes which were RXRA, RBP4, HSD11B1 and AKR1C1 showed remarkable co-expression and predominantly involved in steroid metabolic process. Furthermore, among these 20 genes, 13 highly expressed genes associated with xenobiotics by cytochrome P450, chemical carcinogenesis and steroid metabolic pathways were identified through gene ontology (GO) and KEGG pathway analysis. In conclusion, XNT is targeting multiple proteins and pathways which may be exploited to shape a network that exerts systematic pharmacological effects.
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http://dx.doi.org/10.1038/s41598-021-81026-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810825PMC
January 2021

The effects of Piper sarmentosum aqueous extracts on zebrafish (Danio rerio) embryos and caudal fin tissue regeneration.

Sci Rep 2020 08 25;10(1):14165. Epub 2020 Aug 25.

Department of Biological Sciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600, Bangi, Selangor, Malaysia.

In Malaysia, Piper sarmentosum or 'kaduk' is commonly used in traditional medicines. However, its biological effects including in vivo embryonic toxicity and tissue regenerative properties are relatively unknown. The purpose of this study was to determine zebrafish (Danio rerio) embryo toxicities and caudal fin tissue regeneration in the presence of P. sarmentosum aqueous extracts. The phytochemical components and antioxidant activity of the extract were studied using GC-MS analysis and DPPH assay, respectively. Embryo toxicity tests involving survival, heartbeat, and morphological analyses were conducted to determine P. sarmentosum extract toxicity (0-60 µg/mL); concentrations of 0-400 µg/mL of the extract were used to study tissue regeneration in the zebrafish caudal fin. The extract contained several phytochemicals with antioxidant activity and exhibited DPPH scavenging activity (IC = 50.56 mg/mL). Embryo toxicity assays showed that a concentration of 60 μg/mL showed the highest rates of lethality regardless of exposure time. Slower embryogenesis was observed at 40 µg/mL, with non-viable embryos first detected at 50 µg/mL. Extracts showed significant differences (p < 0.01) for tissue regeneration at all concentrations when compared to non-treated samples. In conclusion, Piper sarmentosum extracts accelerated tissue regeneration, and extract concentrations at 60 µg/mL showed the highest toxicity levels for embryo viability.
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http://dx.doi.org/10.1038/s41598-020-70962-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447815PMC
August 2020

In silico analysis on the functional and structural impact of Rad50 mutations involved in DNA strand break repair.

PeerJ 2020 22;8:e9197. Epub 2020 May 22.

Department of Food Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia.

Background: DNA double strand break repair is important to preserve the fidelity of our genetic makeup after DNA damage. Rad50 is one of the components in MRN complex important for DNA repair mechanism. Rad50 mutations can lead to microcephaly, mental retardation and growth retardation in human. However, Rad50 mutations in human and other organisms have never been gathered and heuristically compared for their deleterious effects. It is important to assess the conserved region in Rad50 and its homolog to identify vital mutations that can affect functions of the protein.

Method: In this study, Rad50 mutations were retrieved from SNPeffect 4.0 database and literature. Each of the mutations was analyzed using various bioinformatic analyses such as PredictSNP, MutPred, SNPeffect 4.0, I-Mutant and MuPro to identify its impact on molecular mechanism, biological function and protein stability, respectively.

Results: We identified 103 mostly occurred mutations in the Rad50 protein domains and motifs, which only 42 mutations were classified as most deleterious. These mutations are mainly situated at the specific motifs such as Walker A, Q-loop, Walker B, D-loop and signature motif of the Rad50 protein. Some of these mutations were predicted to negatively affect several important functional sites that play important roles in DNA repair mechanism and cell cycle signaling pathway, highlighting Rad50 crucial role in this process. Interestingly, mutations located at non-conserved regions were predicted to have neutral/non-damaging effects, in contrast with previous experimental studies that showed deleterious effects. This suggests that software used in this study may have limitations in predicting mutations in non-conserved regions, implying further improvement in their algorithm is needed. In conclusion, this study reveals the priority of acid substitution associated with the genetic disorders. This finding highlights the vital roles of certain residues such as K42E, C681A/S, CC684R/S, S1202R, E1232Q and D1238N/A located in Rad50 conserved regions, which can be considered for a more targeted future studies.
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http://dx.doi.org/10.7717/peerj.9197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247530PMC
May 2020

Alcoholic fermentation of soursop (Annona muricata) juice via an alternative fermentation technique.

J Sci Food Agric 2020 Feb 26;100(3):1012-1021. Epub 2019 Nov 26.

Department of Food Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor, Malaysia.

Background: Wines are produced via the alcoholic fermentation of suitable substrates, usually sugar (sugar cane, grapes) and carbohydrates (wheat, grain). However, conventional alcoholic fermentation is limited by the inhibition of yeast by ethanol produced, usually at approximately 13-14%. Aside from that, soursop fruit is a very nutritious fruit, although it is highly perishable, and thus produces a lot of wastage. Therefore, the present study aimed to produce fermented soursop juice (soursop wine), using combination of two starter cultures, namely mushroom (Pleurotus pulmonarius) and yeast (Saccharomyces cerevisiae), as well as to determine the effects of fermentation on the physicochemical and antioxidant activities of fermented soursop juice. Optimisation of four factors (pH, temperature, time and culture ratio) using response surface methodology were performed to maximise ethanol production.

Results: The optimised values for alcoholic fermentation were pH 4.99, 28.29 °C, 131 h and a 0.42 culture ratio (42:58, P. pulmonarius mycelia:S. cerevisiae) with a predicted ethanol concentration of 22.25%. Through a verification test, soursop wine with 22.29 ± 0.52% ethanol was produced. The antioxidant activities (1,1-diphenyl-2-picrylhydrazyl and ferric reducing antioxidant power) showed a significant (P < 0.05) increase from the soursop juice to soursop wine.

Conclusion: The alternative fermentation technique using yeast and mushroom has successfully been optimised, with an increased ethanol production in soursop wine and higher antioxidant activities. Ultimately, this finding has high potential for application in the brewing industry to enhance the fermentation process, as well as in the development of an innovative niche product, reducing wastage by converting the highly-perishable fruit into wine with a more stable and longer shelf-life. © 2019 Society of Chemical Industry.
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http://dx.doi.org/10.1002/jsfa.10103DOI Listing
February 2020

Comparative genome analysis reveals a distinct influence of nucleotide composition on virus-host species-specific interaction of prawn-infecting nodavirus.

J Fish Dis 2019 Dec 21;42(12):1761-1772. Epub 2019 Oct 21.

Institute of Systems Biology, Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia.

Discovery of species-specific interaction between the host and virus has drawn the interest of many researchers to study the evolution of the newly emerged virus. Comparative genome analysis provides insights of the virus functional genome evolution and the underlying mechanisms of virus-host interactions. The analysis of nucleotide composition signified the evolution of nodavirus towards host specialization in a host-specific mutation manner. GC-rich genome of betanodavirus was significantly deficient in UpA and UpU dinucleotides composition, whilst the AU-rich genome of gammanodavirus was deficient in CpG dinucleotide. The capsid of MrNV and PvNV of gammanodavirus retains the highest abundance of adenine and uracil at the second codon position, respectively, which were found to be very distinctive from the other genera. ENC-GC3 plot inferred the influence of natural selection and mutational pressure in shaping the evolution of MrNV RdRp and capsid, respectively. Furthermore, CAI/eCAI analysis predicts a comparable adaptability of MrNV in squid, Sepia officinalis than its natural host, Macrobrachium rosenbergii. Thus, further study is warranted to investigate the capacity of MrNV replication in S. officinalis owing to its high codon adaptation index.
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http://dx.doi.org/10.1111/jfd.13093DOI Listing
December 2019

Cytotoxicity and Toxicity Evaluation of Xanthone Crude Extract on Hypoxic Human Hepatocellular Carcinoma and Zebrafish () Embryos.

Toxics 2018 Oct 9;6(4). Epub 2018 Oct 9.

Danish Cancer Society Research Centre, Strandboulevarden 49, 2100 Copenhagen, Denmark.

Xanthone is an organic compound mostly found in mangosteen pericarp and widely known for its anti-proliferating effect on cancer cells. In this study, we evaluated the effects of xanthone crude extract (XCE) and α-mangostin (α-MG) on normoxic and hypoxic human hepatocellular carcinoma (HepG2) cells and their toxicity towards zebrafish embryos. XCE was isolated using a mixture of acetone and water (80:20) and verified via high performance liquid chromatography (HPLC). Both XCE and α-MG showed higher anti-proliferation effects on normoxic HepG2 cells compared to the control drug, 5-fluorouracil (IC = 50.23 ± 1.38, 8.39 ± 0.14, and 143.75 ± 15.31 μg/mL, respectively). In hypoxic conditions, HepG2 cells were two times less sensitive towards XCE compared to normoxic HepG2 cells (IC = 109.38 ± 1.80 μg/mL) and three times less sensitive when treated with >500 μg/mL 5-fluorouracil (5-FU). A similar trend was seen with the α-MG treatment on hypoxic HepG2 cells (IC = 10.11 ± 0.05 μg/mL) compared to normoxic HepG2 cells. However, at a concentration of 12.5 μg/mL, the α-MG treatment caused tail-bend deformities in surviving zebrafish embryos, while no malformation was observed when embryos were exposed to XCE and 5-FU treatments. Our study suggests that both XCE and α-MG are capable of inhibiting HepG2 cell proliferation during normoxic and hypoxic conditions, more effectively than 5-FU. However, XCE is the preferred option as no malformation was observed in surviving zebrafish embryos and it is more cost efficient than α-MG.
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http://dx.doi.org/10.3390/toxics6040060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316214PMC
October 2018

ATM inhibition prevents interleukin-6 from contributing to the proliferation of glioblastoma cells after ionizing radiation.

J Neurooncol 2018 Jul 21;138(3):509-518. Epub 2018 Mar 21.

Translational Brain Cancer Research Laboratory, Cell and Molecular Biology Department, QIMR Berghofer MRI, 300 Herston Rd, Brisbane, QLD, 4006, Australia.

Glioblastoma (GBM) is a highly fatal disease with a 5 year survival rate of less than 22%. One of the most effective treatment regimens to date is the use of radiotherapy which induces lethal DNA double-strand breaks to prevent tumour growth. However, recurrence occurs in the majority of patients and is in-part a result of robust radioresistance mechanisms. In this study, we demonstrate that the multifunctional cytokine, interleukin-6 (IL-6), confers a growth advantage in GBM cells but does not have the same effect on normal neural progenitor cells. Further analysis showed IL-6 can promote radioresistance in GBM cells when exposed to ionising radiation. Ablation of the Ataxia-telangiectasia mutated serine/threonine kinase that is recruited and activated by DNA double-strand breaks reverses the effect of radioresistance and re-sensitised GBM to DNA damage thus leading to increase cell death. Our finding suggests targeting the signaling cascade of DNA damage response is a potential therapeutic approach to circumvent IL-6 from promoting radioresistance in GBM.
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http://dx.doi.org/10.1007/s11060-018-2838-0DOI Listing
July 2018

Modified Dioscorea hispida starch-based hydrogels and their in-vitro cytotoxicity study on small intestine cell line (FHS-74 Int).

Int J Biol Macromol 2018 Feb 19;107(Pt B):2412-2421. Epub 2017 Oct 19.

School of Chemical Sciences and Food Technology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia. Electronic address:

Starch-based hydrogels are promising smart materials for biomedical and pharmaceutical applications, which offer exciting perspectives in biophysical research at molecular level. This work was intended to develop, characterize and explore the properties of hydrogel from starch extracted from new source, Dioscorea hispida Dennst. Starch-mediated hydrogels were successfully synthesized via free radical polymerization method with varying concentrations of acrylic acid (AA),N,N'-methylenebisacrylamide (MBA) and sodium hydroxide (NaOH) in aqueous system. The grafting reaction between starch and AA was examined by observing the decline in intensity peak of hydrogel FTIR spectrum at 3291cm and peak around 1600-1680cm, indicating the stretching of hydroxyl group (OH) and stretching of carbon-carbon double bond (CC) respectively. The effects of cross-linker, monomer and NaOH concentration on swelling ratio and gel content in different medium and conditions were also evaluated. The thermal stability and structural morphology of as-synthesized hydrogels were studied by thermogravimetry analysis (TGA) and scanning electron microscopy (SEM). In-vitro cytotoxicity study using small intestine cell line (FHS-74 Int) revealed that the as-formulated eco-friendly-hydrogel was free from any harmful material and safe to use for future product development.
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http://dx.doi.org/10.1016/j.ijbiomac.2017.10.125DOI Listing
February 2018

Varieties, production, composition and health benefits of vinegars: A review.

Food Chem 2017 Apr 31;221:1621-1630. Epub 2016 Oct 31.

School of Chemical Sciences and Food Technology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor, Malaysia. Electronic address:

Vinegars are liquid products produced from the alcoholic and subsequent acetous fermentation of carbohydrate sources. They have been used as remedies in many cultures and have been reported to provide beneficial health effects when consumed regularly. Such benefits are due to various types of polyphenols, micronutrients and other bioactive compounds found in vinegars that contribute to their pharmacological effects, among them, antimicrobial, antidiabetic, antioxidative, antiobesity and antihypertensive effects. There are many types of vinegars worldwide, including black vinegar, rice vinegar, balsamic vinegar and white wine vinegar. All these vinegars are produced using different raw materials, yeast strains and fermentation procedures, thus giving them their own unique tastes and flavours. The main volatile compound in vinegar is acetic acid, which gives vinegar its strong, sour aroma and flavour. Other volatile compounds present in vinegars are mainly alcohols, acids, esters, aldehydes and ketones. The diversity of vinegars allows extensive applications in food.
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http://dx.doi.org/10.1016/j.foodchem.2016.10.128DOI Listing
April 2017

Physicochemical Properties of Starch from Dioscorea pyrifolia tubers.

Food Chem 2017 Apr 30;220:225-232. Epub 2016 Sep 30.

School of Biosciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia.

Starch from Dioscorea pyrifolia tubers was characterized for its proximate composition, physicochemical properties and toxicity. This starch contains 44.47±1.86% amylose, 4.84±0.29% moisture, 0.88±0.21% ash, 1.34±0.11% proteins and 92.73±0.48% carbohydrates. X-ray diffraction (XRD) analysis showed a type-C starch with a relative crystallinity of 23.31±2.41%. The starch granules are polyhedral, with a diameter of 2.8 to 5.6μm and average size of 3.93±1.47μm. Initial, peak and finishing gelatinization temperatures for the starch were 71.51±0.07, 75.05±0.15, and 78.25±0.18°C, respectively; the gelatinization enthalpy was 3.86±0.02J/g, and the peak height index was 1.09±0.05. Thermogravimetric analysis showed a weight loss of 85.81±0.52% and a decomposition temperature of 320.16±0.35°C, which indicated that there was good thermal stability of the starch. Fish embryo toxicity (FET) showed that the starch was not toxic and that it was suitable for food and non-food industries.
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http://dx.doi.org/10.1016/j.foodchem.2016.09.196DOI Listing
April 2017

Transformation of crystalline starch nanoparticles into highly luminescent carbon nanodots: Toxicity studies and their applications.

Carbohydr Polym 2016 Feb 10;137:488-496. Epub 2015 Nov 10.

School of Chemical Sciences and Food Technology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi, 43600 Selangor, Malaysia. Electronic address:

Being abundant in many tropical part of the world, Dioscorea sp. as food is limited due to its toxicity. However polysaccharides derive from these tubers could be important for other applications. Here we developed a Highly Luminescent Carbon Nanodots (C-dots) via acid hydrolysis of Gadong starch (GS). The hydrolysis rate of GS increased from 49% to 86% within 7 days while the X-ray diffraction showed the native GS particle is a C-crystalline type. The GS particles were either round or oval with diameters ranging from 50-90 nm. Further acid dehydration and surface oxidation reduced the size of GS nanoparticles to 6-25 nm. The C-dots produced a fluorescent emission at wavelength 441 nm. Toxicity tests demonstrate that zebrafish embryo were able to tolerate the C-dots for 48 h after exposure. This study has successfully demonstrated a novel approach of converting GS into excellent fluorescent C-dot.
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http://dx.doi.org/10.1016/j.carbpol.2015.11.021DOI Listing
February 2016

Increased sensitivity to ionizing radiation by targeting the homologous recombination pathway in glioma initiating cells.

Mol Oncol 2014 Dec 27;8(8):1603-15. Epub 2014 Jun 27.

QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland 4029, Australia; The University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital Campus, Herston, Queensland 4029, Australia. Electronic address:

Glioblastoma is deemed the most malignant form of brain tumour, particularly due to its resistance to conventional treatments. A small surviving group of aberrant stem cells termed glioma initiation cells (GICs) that escape surgical debulking are suggested to be the cause of this resistance. Relatively quiescent in nature, GICs are capable of driving tumour recurrence and undergo lineage differentiation. Most importantly, these GICs are resistant to radiotherapy, suggesting that radioresistance contribute to their survival. In a previous study, we demonstrated that GICs had a restricted double strand break (DSB) repair pathway involving predominantly homologous recombination (HR) associated with a lack of functional G1/S checkpoint arrest. This unusual behaviour led to less efficient non-homologous end joining (NHEJ) repair and overall slower DNA DSB repair kinetics. To determine whether specific targeting of the HR pathway with small molecule inhibitors could increase GIC radiosensitivity, we used the Ataxia-telangiectasia mutated inhibitor (ATMi) to ablate HR and the DNA-dependent protein kinase inhibitor (DNA-PKi) to inhibit NHEJ. Pre-treatment with ATMi prior to ionizing radiation (IR) exposure prevented HR-mediated DNA DSB repair as measured by Rad51 foci accumulation. Increased cell death in vitro and improved in vivo animal survival could be observed with combined ATMi and IR treatment. Conversely, DNA-PKi treatment had minimal impact on GICs ability to resolve DNA DSB after IR with only partial reduction in cell survival, confirming the major role of HR. These results provide a mechanistic insight into the predominant form of DNA DSB repair in GICs, which when targeted may be a potential translational approach to increase patient survival.
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http://dx.doi.org/10.1016/j.molonc.2014.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5528585PMC
December 2014

ATM protein-dependent phosphorylation of Rad50 protein regulates DNA repair and cell cycle control.

J Biol Chem 2011 Sep 14;286(36):31542-56. Epub 2011 Jul 14.

Radiation Biology and Oncology Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia.

The Mre11/Rad50/NBN complex plays a central role in coordinating the cellular response to DNA double-strand breaks. The importance of Rad50 in that response is evident from the recent description of a patient with Rad50 deficiency characterized by chromosomal instability and defective ATM-dependent signaling. We report here that ATM (defective in ataxia-telangiectasia) phosphorylates Rad50 at a single site (Ser-635) that plays an important adaptor role in signaling for cell cycle control and DNA repair. Although a Rad50 phosphosite-specific mutant (S635G) supported normal activation of ATM in Rad50-deficient cells, it was defective in correcting DNA damage-induced signaling through the ATM-dependent substrate SMC1. This mutant also failed to correct radiosensitivity, DNA double-strand break repair, and an S-phase checkpoint defect in Rad50-deficient cells. This was not due to disruption of the Mre11/Rad50/NBN complex revealing for the first time that phosphorylation of Rad50 plays a key regulatory role as an adaptor for specific ATM-dependent downstream signaling through SMC1 for DNA repair and cell cycle checkpoint control in the maintenance of genome integrity.
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http://dx.doi.org/10.1074/jbc.M111.258152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173097PMC
September 2011