The role of H3K9me2 ‐regulated base excision repair genes in the repair of DNA damage induced by arsenic in HaCaT cells and the effects of Ginkgo biloba extract intervention

2020 ◽  
Author(s):  
Xuejiao Ding ◽  
Anliu Zhang ◽  
Changzhe Li ◽  
Lu Ma ◽  
Shunfang Tang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Base Excision Repair ◽  
Ginkgo Biloba ◽  
Excision Repair ◽  
Ginkgo Biloba Extract ◽  
Hacat Cells ◽  
Base Excision ◽  
Repair Genes

scholarly journals Role of Base Excision Repair Pathway in the Processing of Complex DNA Damage Generated by Oxidative Stress and Anticancer Drugs

2021 ◽  
Vol 8 ◽  
Author(s):  
Yeldar Baiken ◽  
Damira Kanayeva ◽  
Sabira Taipakova ◽  
Regina Groisman ◽  
Alexander A. Ishchenko ◽  
...  
Keyword(s):  
Dna Damage ◽  
Base Excision Repair ◽  
Genome Instability ◽  
Excision Repair ◽  
Chromosomal Rearrangements ◽  
Strand Break ◽  
Dna Lesions ◽  
Complex Nature ◽  
Base Excision

Chemical alterations in DNA induced by genotoxic factors can have a complex nature such as bulky DNA adducts, interstrand DNA cross-links (ICLs), and clustered DNA lesions (including double-strand breaks, DSB). Complex DNA damage (CDD) has a complex character/structure as compared to singular lesions like randomly distributed abasic sites, deaminated, alkylated, and oxidized DNA bases. CDD is thought to be critical since they are more challenging to repair than singular lesions. Although CDD naturally constitutes a relatively minor fraction of the overall DNA damage induced by free radicals, DNA cross-linking agents, and ionizing radiation, if left unrepaired, these lesions cause a number of serious consequences, such as gross chromosomal rearrangements and genome instability. If not tightly controlled, the repair of ICLs and clustered bi-stranded oxidized bases via DNA excision repair will either inhibit initial steps of repair or produce persistent chromosomal breaks and consequently be lethal for the cells. Biochemical and genetic evidences indicate that the removal of CDD requires concurrent involvement of a number of distinct DNA repair pathways including poly(ADP-ribose) polymerase (PARP)-mediated DNA strand break repair, base excision repair (BER), nucleotide incision repair (NIR), global genome and transcription coupled nucleotide excision repair (GG-NER and TC-NER, respectively), mismatch repair (MMR), homologous recombination (HR), non-homologous end joining (NHEJ), and translesion DNA synthesis (TLS) pathways. In this review, we describe the role of DNA glycosylase-mediated BER pathway in the removal of complex DNA lesions.

Role Of Base Excision Repair Associated AP Nuclease Activity In The Induction Of Homologous Recombination Repair Pathway and Survival Of MM Cells Following DNA Damage

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1248-1248
Author(s):  
Subodh Kumar ◽  
Jagannath Pal ◽  
Jialan Shi ◽  
Puru Nanjappa ◽  
Maria Gkotzamanidou ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Critical Role ◽  
Nuclease Activity ◽  
Repair Pathway ◽  
Control Shrna ◽  
Base Excision

Abstract We have previously shown that endonuclease activity is deregulated in myeloma and suppression of base excision repair (BER) associated apurinic/apyrimidinic endonuclease (APE) activity, mediated chemically or transgenically, reduces homologous recombination (HR) and genomic instability in multiple myeloma (MM). The purpose of this study was to investigate the role of BER-specific AP nucleases APE1 and APE2, separately or together, in the activation of HR pathway following exposure of MM cells to different DNA damaging agents and unravel possible mechanism/s and translational significance of this cross talk between two repair pathways in MM. We transduced MM cells with lentivirus-based shRNAs, either control (CS) or those targeting APE1, APE2, or both (APE1/2; double knockdown) and selected the transduced cells in puromycin. Knockdowns were confirmed by Western blotting and Q-PCR. Using evaluation by Q-PCR we observed that whereas APE2 was suppressed by 80% in APE2- as well as double-knockdown cells, it was upregulated by 70% in APE1 knock down cells. These data indicate that certain level of AP nuclease activity is probably required by MM cell to function and is consistent with a 25-30% reduced proliferation rate of double-knockdown cells under spontaneous condition. To study the impact of these modulations on ability of cells to activate HR-mediated repair pathway in response to DNA damage, the cells were exposed to either UV (20 J/m2) and incubated for 2 and 48 hrs or melphalan (2.5 µM) treatment for 24 hrs, and then incubation for further 1 and 24 hrs and evaluated for RAD51 and γ-H2AX foci. Following UV treatment, RAD51 foci were detected in 91%, 48%, 49%, and 28% of cells transduced with control, APE1, APE2, or both shRNAs, respectively. Similary melphalan treatment induced RAD51 foci in 76% of control shRNA transduced cells whereas only in 46%, 47%, and 27% of APE1, APE2, and APE1/2-knockdown cells. These data show that AP nuclease activity is involved in DNA damaging agent-induced activation of HR repair pathway. Impact of the suppression of AP nucleases was also assessed on cell proliferation at 48 hrs after treatment with melphalan. Viability of cells lacking APE1, APE2, and APE1/2 relative to control shRNA-transduced cells was reduced by 28%, 26%, and 43% (P<0.00005), respectively, within 48 hrs of treatment. In summary, we show that: 1) AP nuclease activity plays a critical role in the activation of HR-mediated DNA repair and survival of MM cells following DNA damage; 2) Although suppression of APE1 or APE2 alone does not significantly affect spontaneous proliferation rates, simultaneous suppression of both reduces proliferation by ∼25-30%; 3) Suppression of APE1 leads to induction of APE2, indicating that certain level of AP nuclease activity (from either APE1 or APE2) is required by MM cell to function and is consistent with the reduced proliferation rate of double-knockdown cells; 4) Simultaneous suppression of both AP nucleases impairs the activation of HR repair following DNA damage. These data combined with our previous observations conclude that AP nucleases (APE1 and APE2) play critical role in HR-mediated repair and survival of MM cells following DNA damage and are important targets to reduce genomic instability as well as to sensitize MM cells to radio/chemotherapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Impact of Single Nucleotide Polymorphisms of Base Excision Repair Genes on DNA Damage and Efficiency of DNA Repair in Recurrent Depression Disorder

2016 ◽  
Vol 54 (6) ◽  
pp. 4150-4159 ◽  
Author(s):  
Piotr Czarny ◽  
Dominik Kwiatkowski ◽  
Monika Toma ◽  
Joanna Kubiak ◽  
Agnieszka Sliwinska ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Nucleotide Polymorphisms ◽  
Recurrent Depression ◽  
Single Nucleotide ◽  
Base Excision ◽  
Repair Genes ◽  
Depression Disorder

scholarly journals Oxidative Damage in Sporadic Colorectal Cancer: Molecular Mapping of Base Excision Repair Glycosylases in Colorectal Cancer Patients

2020 ◽  
Vol 21 (7) ◽  
pp. 2473 ◽  
Author(s):  
Pavel Vodicka ◽  
Marketa Urbanova ◽  
Pavol Makovicky ◽  
Kristyna Tomasova ◽  
Michal Kroupa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Base Excision Repair ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Sporadic Colorectal Cancer ◽  
Base Excision ◽  
Colorectal Cancer Patients

Oxidative stress with subsequent premutagenic oxidative DNA damage has been implicated in colorectal carcinogenesis. The repair of oxidative DNA damage is initiated by lesion-specific DNA glycosylases (hOGG1, NTH1, MUTYH). The direct evidence of the role of oxidative DNA damage and its repair is proven by hereditary syndromes (MUTYH-associated polyposis, NTHL1-associated tumor syndrome), where germline mutations cause loss-of-function in glycosylases of base excision repair, thus enabling the accumulation of oxidative DNA damage and leading to the adenoma-colorectal cancer transition. Unrepaired oxidative DNA damage often results in G:C>T:A mutations in tumor suppressor genes and proto-oncogenes and widespread occurrence of chromosomal copy-neutral loss of heterozygosity. However, the situation is more complicated in complex and heterogeneous disease, such as sporadic colorectal cancer. Here we summarized our current knowledge of the role of oxidative DNA damage and its repair on the onset, prognosis and treatment of sporadic colorectal cancer. Molecular and histological tumor heterogeneity was considered. Our study has also suggested an additional important source of oxidative DNA damage due to intestinal dysbiosis. The roles of base excision repair glycosylases (hOGG1, MUTYH) in tumor and adjacent mucosa tissues of colorectal cancer patients, particularly in the interplay with other factors (especially microenvironment), deserve further attention. Base excision repair characteristics determined in colorectal cancer tissues reflect, rather, a disease prognosis. Finally, we discuss the role of DNA repair in the treatment of colon cancer, since acquired or inherited defects in DNA repair pathways can be effectively used in therapy.

scholarly journals The role of base excision repair genes OGG1, APN1 and APN2 in benzo[a]pyrene-7,8-dione induced p53 mutagenesis

2013 ◽  
Vol 750 (1-2) ◽  
pp. 121-128 ◽  
Author(s):  
Zahidur Abedin ◽  
Melissa Louis-Juste ◽  
Melissa Stangl ◽  
Jeffrey Field
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Base Excision ◽  
Repair Genes

Antimutagenic role of base-excision repair enzymes upon free radical-induced DNA damage

1998 ◽  
Vol 402 (1-2) ◽  
pp. 93-102 ◽  
Author(s):  
Jacques Laval ◽  
Juan Jurado ◽  
Murat Saparbaev ◽  
Olga Sidorkina
Keyword(s):  
Dna Damage ◽  
Free Radical ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Repair Enzymes ◽  
Base Excision

scholarly journals Role of Oligoadenylate Synthetases in Myeloid Neoplasia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-30
Author(s):  
Metis Hasipek ◽  
Yihong Guan ◽  
Dale Grabowski ◽  
Xiaorong Gu ◽  
Yogenthiran Saunthararajah ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Over Expression ◽  
Myeloid Leukemias ◽  
Base Excision ◽  
Acute Myeloid ◽  
Novel Therapeutic

Acute myeloid leukemias (AML), the most lethal forms of blood cancer, are genomic instability disorders primarily driven by somatic mutations that greatly impact proliferation and survival of mutant clones1. The multistep mechanism of disease progression can be attributed, in part, to the defects in one or more pathways involving responses to, or repair of, damaged DNA (DD) and base excision repair (BER). The basal levels of DD and BER are higher in myeloid leukemias due to higher levels of reactive oxygen species (ROS)-mediated accumulation of 8-oxyguanine (8-OG)2. Poly(ADP) Ribosylation (PARylation) by PAR polymerases (PARPs) is one of the early key steps in sensing and repairing ROS-induced DNA damage response (DDR) 3. Consistent with recent findings4,5 here we report that 2'-5'oligoadenylate synthases (OASs), a family of latent 2'-5'-adenylyl transferases, otherwise involved in cellular antiviral responses6, are also involved in PAR remodeling of the DDR in MDS and AML cells. The 2'-hydroxyl group of PAR ribose acts as an acceptor for 2'AMP in the OAS enzymatic reaction and terminates chain elongation (Fig. A). OAS1 over expression can increase genomic instability by increasing the flux of PARP-mediated DNA repair, promoting cellular proliferation (Fig. B)5. Expression analysis of OASs in AML patients (n=451, Beat AML) showed that OAS1 is upregulated (2-fold) in AML patients compared to normal bone marrow-derived CD34+ hematopoietic stem and progenitor cells (HSPC)(Fig. C). Knockout of OAS1 and OAS2 using Crispr-Cas9 in MDS-L cells (Fig. D), a cell line derived from an MDS patient, confers sensitivity to H2O2-induced DNA damage-mediated cell death; however, OAS3 has no effect. Conversely, ectopic over expression of OAS1 or OAS2 but not OAS3 in HEK293 cells provides protection against H2O2-induced cell death (Fig. E-F). Proteomic analysis of the OAS1 and OAS2 interactome using LCMS/MS suggests that over expression of OAS1 and OAS2 perturbs the differentiation program of HSPCs that may result in neoplastic evolution. Thus, OASs modify PAR chains, promoting speedy DNA repair and cell survival along with the induction of a differentiation block in HSPCs that leads to clonal expansion. In summary, an overburdened DDR may contribute to AML pathogenesis. Therefore, inhibiting this stimulator of BER/DDR can provide a novel therapeutic avenue in myeloid neoplasms. The current study points to the probable utility of a novel therapeutic approach of targeting OAS in combination with DNA damaging agents to prevent relapse and resistance in the treatment of leukemias. References 1. Abelson S, Collord G, Ng SWK, et al. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature. 2018;559(7714):400-404. doi:10.1038/s41586-018-0317-6 2. Jankowska AM, Gondek LP, Szpurka H, Nearman ZP, Tiu RV, Maciejewski JP. Base excision repair dysfunction in a subgroup of patients with myelodysplastic syndrome. Leukemia. 2008;22(3):551-558. doi:10.1038/sj.leu.2405055 3. Rogge RA, Gibson BA, Kraus WL. Identifying Genomic Sites of ADP-Ribosylation Mediated by Specific Nuclear PARP Enzymes Using Click-ChIP. Methods Mol Biol. 2018;1813:371-387. doi:10.1007/978-1-4939-8588-3_25 4. Khodarev NN, Minn AJ, Efimova EV, et al. Signal transducer and activator of transcription 1 regulates both cytotoxic and prosurvival functions in tumor cells. Cancer Res. 2007;67(19):9214-9220. doi:10.1158/0008-5472.CAN-07-1019 5. Kondratova AA, Cheon H, Dong B, et al. Suppressing PARylation by 2',5'-oligoadenylate synthetase 1 inhibits DNA damage-induced cell death. EMBO J. 2020;39(11):e101573. doi:10.15252/embj.2019101573 6. Chakrabarti A, Jha BK, Silverman RH. New insights into the role of RNase L in innate immunity. J Interferon Cytokine Res. 2011;31(1):49-57. doi:10.1089/jir.2010.0120 Disclosures Saunthararajah: EpiDestiny: Consultancy, Current equity holder in private company, Patents & Royalties: University of Illinois at Chicago.

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