Education & Certifications

  • MS, Engineer-Physicist, Moscow Institute of Physics and Technology, Applied Math and Physics (1990)
  • PhD, Colorado State University, Cell and Molecular Radiation Biology (1998)


  • • Role of microtubule-dependent cell trafficking in DNA repair and chemotherapy response of estrogen-negative breast cancer


    Stanford University

  • • Testing the efficacy of inhibitors of stromal derived factor 1 (SDF-1) pathway in post-irradiation treatment of breast cancer brain metastases


    Stanford University

  • • Role of SDF-1 mediated pathway in glioblastoma recurrence after whole-brain irradiation, Stanford University


    Stanford University

  • • Role of chromatin remodeling in radiation response and genomic instability


    Stanford University

  • • Development of a compound library screen aimed at finding small-molecule inhibitors of homologous recombination


    Stanford University

  • • Investigating mechanisms of action of hypoxia-activated cytotoxins, including the dinitrobenzamide mustard PR104A and tirapazamine

    Identified homologous recombination pathway as a main pathway for repair of damage induced by a tirapazamine.


    Stanford University

All Publications

  • Dynamin impacts homology-directed repair and breast cancer response to chemotherapy. The Journal of clinical investigation Chernikova, S. B., Nguyen, R. B., Truong, J. T., Mello, S. S., Stafford, J. H., Hay, M. P., Olson, A. n., Solow-Cordero, D. E., Wood, D. J., Henry, S. n., von Eyben, R. n., Deng, L. n., Gephart, M. H., Aroumougame, A. n., Wiese, C. n., Game, J. C., Győrffy, B. n., Brown, J. M. 2018


    After the initial responsiveness of triple-negative breast cancers (TNBCs) to chemotherapy, they often recur as chemotherapy-resistant tumors, and this has been associated with upregulated homology-directed repair (HDR). Thus, inhibitors of HDR could be a useful adjunct to chemotherapy treatment of these cancers. We performed a high-throughput chemical screen for inhibitors of HDR from which we obtained a number of hits that disrupted microtubule dynamics. We postulated that high levels of the target molecules of our screen in tumors would correlate with poor chemotherapy response. We found that inhibition or knockdown of dynamin 2 (DNM2), known for its role in endocytic cell trafficking and microtubule dynamics, impaired HDR and improved response to chemotherapy of cells and of tumors in mice. In a retrospective analysis, levels of DNM2 at the time of treatment strongly predicted chemotherapy outcome for estrogen receptor-negative and especially for TNBC patients. We propose that DNM2-associated DNA repair enzyme trafficking is important for HDR efficiency and is a powerful predictor of sensitivity to breast cancer chemotherapy and an important target for therapy.

    View details for PubMedID 30371505

  • Single-Cell RNA-Seq Analysis of Infiltrating Neoplastic Cells at the Migrating Front of Human Glioblastoma. Cell reports Darmanis, S. n., Sloan, S. A., Croote, D. n., Mignardi, M. n., Chernikova, S. n., Samghababi, P. n., Zhang, Y. n., Neff, N. n., Kowarsky, M. n., Caneda, C. n., Li, G. n., Chang, S. D., Connolly, I. D., Li, Y. n., Barres, B. A., Gephart, M. H., Quake, S. R. 2017; 21 (5): 1399–1410


    Glioblastoma (GBM) is the most common primary brain cancer in adults and is notoriously difficult to treat because of its diffuse nature. We performed single-cell RNA sequencing (RNA-seq) on 3,589 cells in a cohort of four patients. We obtained cells from the tumor core as well as surrounding peripheral tissue. Our analysis revealed cellular variation in the tumor's genome and transcriptome. We were also able to identify infiltrating neoplastic cells in regions peripheral to the core lesions. Despite the existence of significant heterogeneity among neoplastic cells, we found that infiltrating GBM cells share a consistent gene signature between patients, suggesting a common mechanism of infiltration. Additionally, in investigating the immunological response to the tumors, we found transcriptionally distinct myeloid cell populations residing in the tumor core and the surrounding peritumoral space. Our data provide a detailed dissection of GBM cell types, revealing an abundance of information about tumor formation and migration.

    View details for PubMedID 29091775

  • Colony stimulating factor 1 receptor inhibition delays recurrence of glioblastoma after radiation by altering myeloid cell recruitment and polarization NEURO-ONCOLOGY Stafford, J. H., Hirai, T., Deng, L., Chernikova, S. B., Urata, K., West, B. L., Brown, J. M. 2016; 18 (6): 797-806


    Glioblastoma (GBM) may initially respond to treatment with ionizing radiation (IR), but the prognosis remains extremely poor because the tumors invariably recur. Using animal models, we previously showed that inhibiting stromal cell-derived factor 1 signaling can prevent or delay GBM recurrence by blocking IR-induced recruitment of myeloid cells, specifically monocytes that give rise to tumor-associated macrophages. The present study was aimed at determining if inhibiting colony stimulating factor 1 (CSF-1) signaling could be used as an alternative strategy to target pro-tumorigenic myeloid cells recruited to irradiated GBM.To inhibit CSF-1 signaling in myeloid cells, we used PLX3397, a small molecule that potently inhibits the tyrosine kinase activity of the CSF-1 receptor (CSF-1R). Combined IR and PLX3397 therapy was compared with IR alone using 2 different human GBM intracranial xenograft models.GBM xenografts treated with IR upregulated CSF-1R ligand expression and increased the number of CD11b+ myeloid-derived cells in the tumors. Treatment with PLX3397 both depleted CD11b+ cells and potentiated the response of the intracranial tumors to IR. Median survival was significantly longer for mice receiving combined therapy versus IR alone. Analysis of myeloid cell differentiation markers indicated that CSF-1R inhibition prevented IR-recruited monocyte cells from differentiating into immunosuppressive, pro-angiogenic tumor-associated macrophages.CSF-1R inhibition may be a promising strategy to improve GBM response to radiotherapy.

    View details for DOI 10.1093/neuonc/nov272

    View details for Web of Science ID 000376151200012

    View details for PubMedID 26538619

  • Inhibition of CXCR7 extends survival following irradiation of brain tumours in mice and rats BRITISH JOURNAL OF CANCER Walters, M. J., Ebsworth, K., Berahovich, R. D., Penfold, M. E., Liu, S., Al Omran, R., Kioi, M., Chernikova, S. B., Tseng, D., Mulkearns-Hubert, E. E., Sinyuk, M., Ransohoff, R. M., Lathia, J. D., Karamchandani, J., Kohrt, H. E., Zhang, P., Powers, J. P., Jaen, J. C., Schall, T. J., Merchant, M., Recht, L., Brown, J. M. 2014; 110 (5): 1179-1188


    In experimental models of glioblastoma multiforme (GBM), irradiation (IR) induces local expression of the chemokine CXCL12/SDF-1, which promotes tumour recurrence. The role of CXCR7, the high-affinity receptor for CXCL12, in the tumour's response to IR has not been addressed.We tested CXCR7 inhibitors for their effects on tumour growth and/or animal survival post IR in three rodent GBM models. We used immunohistochemistry to determine where CXCR7 protein is expressed in the tumours and in human GBM samples. We used neurosphere formation assays with human GBM xenografts to determine whether CXCR7 is required for cancer stem cell (CSC) activity in vitro. RESULTS :CXCR7 was detected on tumour cells and/or tumour-associated vasculature in the rodent models and in human GBM. In human GBM, CXCR7 expression increased with glioma grade and was spatially associated with CXCL12 and CXCL11/I-TAC. In the rodent GBM models, pharmacological inhibition of CXCR7 post IR caused tumour regression, blocked tumour recurrence, and/or substantially prolonged survival. CXCR7 expression levels on human GBM xenograft cells correlated with neurosphere-forming activity, and a CXCR7 inhibitor blocked sphere formation by sorted CSCs.These results indicate that CXCR7 inhibitors could block GBM tumour recurrence after IR, perhaps by interfering with CSCs.

    View details for DOI 10.1038/bjc.2013.830

    View details for Web of Science ID 000332836000011

    View details for PubMedID 24423923

    View details for PubMedCentralID PMC3950859

  • Blockade of SDF-1 after irradiation inhibits tumor recurrences of autochthonous brain tumors in rats NEURO-ONCOLOGY Liu, S., Alomran, R., Chernikova, S. B., Lartey, F., Stafford, J., Jang, T., Merchant, M., Zboralski, D., Zoellner, S., Kruschinski, A., Klussmann, S., Recht, L., Brown, J. M. 2014; 16 (1): 21-28


    Background Tumor irradiation blocks local angiogenesis, forcing any recurrent tumor to form new vessels from circulating cells. We have previously demonstrated that the post-irradiation recurrence of human glioblastomas in the brains of nude mice can be delayed or prevented by inhibiting circulating blood vessel-forming cells by blocking the interaction of CXCR4 with its ligand stromal cell-derived factor (SDF)-1 (CXCL12). In the present study we test this strategy by directly neutralizing SDF-1 in a clinically relevant model using autochthonous brain tumors in immune competent hosts. Methods We used NOX-A12, an l-enantiomeric RNA oligonucleotide that binds and inhibits SDF-1 with high affinity. We tested the effect of this inhibitor on the response to irradiation of brain tumors in rat induced by n-ethyl-N-nitrosourea. Results Rats treated in utero with N-ethyl-N-nitrosourea began to die of brain tumors from approximately 120 days of age. We delivered a single dose of whole brain irradiation (20 Gy) on day 115 of age, began treatment with NOX-A12 immediately following irradiation, and continued with either 5 or 20 mg/kg for 4 or 8 weeks, doses and times equivalent to well-tolerated human exposures. We found a marked prolongation of rat life span that was dependent on both drug dose and duration of treatment. In addition we treated tumors only when they were visible by MRI and demonstrated complete regression of the tumors that was not achieved by irradiation alone or with the addition of temozolomide. Conclusions Inhibition of SDF-1 following tumor irradiation is a powerful way of improving tumor response of glioblastoma multiforme.

    View details for DOI 10.1093/neuonc/not149

    View details for PubMedID 24335554

  • R-loops and genomic instability in Bre1 (RNF20/40)-deficient cells CELL CYCLE Chernikova, S. B., Brown, J. M. 2012; 11 (16): 2980-2984


    We have proposed that maintenance of genomic stability may constitute the basis for the tumor-suppressing activity of the Bre1 (RNF20/RNF40) complex. Revisiting the evidence we presented in our recent publication, we discuss the mechanism by which maintenance of genomic stability by the Bre1 complex is achieved through coordination of events during transcription. Among many functions of Bre1, we focus on the two that, when defective, could lead to the formation of R-loops, the RNA:DNA hybrid structures regarded as a major source of genomic instability. Specifically, we discuss the role of Bre1-mediated H2B ubiquitination in the 3'-end processing of replication-associated histone mRNA and in heterochromatic gene silencing and show how disturbance of these two functions may result in the specific pattern of chromosomal abnormalities we observe in the Bre1-depleted cells.

    View details for DOI 10.4161/cc.21090

    View details for Web of Science ID 000308004000014

    View details for PubMedID 22825248

    View details for PubMedCentralID PMC3442907

  • Deficiency in Mammalian Histone H2B Ubiquitin Ligase Bre1 (Rnf20/Rnf40) Leads to Replication Stress and Chromosomal Instability CANCER RESEARCH Chernikova, S. B., Razorenova, O. V., Higgins, J. P., Sishc, B. J., Nicolau, M., Dorth, J. A., Chernikova, D. A., Kwok, S., Brooks, J. D., Bailey, S. M., Game, J. C., Brown, J. M. 2012; 72 (8): 2111-2119


    Mammalian Bre1 complexes (BRE1A/B (RNF20/40) in humans and Bre1a/b (Rnf20/40) in mice) function similarly to their yeast homolog Bre1 as ubiquitin ligases in monoubiquitination of histone H2B. This ubiquitination facilitates methylation of histone H3 at K4 and K79, and accounts for the roles of Bre1 and its homologs in transcriptional regulation. Recent studies by others suggested that Bre1 acts as a tumor suppressor, augmenting expression of select tumor suppressor genes and suppressing select oncogenes. In this study, we present an additional mechanism of tumor suppression by Bre1 through maintenance of genomic stability. We track the evolution of genomic instability in Bre1-deficient cells from replication-associated double-strand breaks (DSB) to specific genomic rearrangements that explain a rapid increase in DNA content and trigger breakage-fusion-bridge cycles. We show that aberrant RNA-DNA structures (R-loops) constitute a significant source of DSBs in Bre1-deficient cells. Combined with a previously reported defect in homologous recombination, generation of R-loops is a likely initiator of replication stress and genomic instability in Bre1-deficient cells. We propose that genomic instability triggered by Bre1 deficiency may be an important early step that precedes acquisition of an invasive phenotype, as we find decreased levels of BRE1A/B and dimethylated H3K79 in testicular seminoma and in the premalignant lesion in situ carcinoma.

    View details for DOI 10.1158/0008-5472.CAN-11-2209

    View details for Web of Science ID 000302905700022

    View details for PubMedID 22354749

    View details for PubMedCentralID PMC3328627

  • Inhibiting homologous recombination for cancer therapy CANCER BIOLOGY & THERAPY Chernikova, S. B., Game, J. C., Brown, J. M. 2012; 13 (2): 61-68


    We review the rationale for seeking inhibitors of homologous recombination (HR) repair for use in cancer therapy. Cells use HR as one way to repair DNA double-strand breaks that arise directly from treatments such as radiotherapy, or indirectly during replication when forks encounter other damage. HR occurs during the S and G 2 phases of the cell cycle and is therefore more significant in dividing cancer cells than in non-dividing cells of healthy tissue, giving a potential therapeutic advantage to inhibiting the process. Also, some tumors consist of cells that are defective in other DNA repair pathways, and such cells may be sensitive to HR repair inhibitors because of synthetic lethality, in which blocking two alternative pathways that a cell can use to reach a needed end-point has a much bigger impact than blocking either pathway alone. We review strategies for identifying HR inhibitors and discuss current progress.

    View details for DOI 10.4161/cbt.13.2.18872

    View details for Web of Science ID 000300357700001

    View details for PubMedID 22336907

    View details for PubMedCentralID PMC3336066

  • The DNA repair endonuclease XPG interacts directly and functionally with the WRN helicase defective in Werner syndrome CELL CYCLE Trego, K. S., Chernikova, S. B., Davalos, A. R., Perry, J. J., Finger, L. D., Ng, C., Tsai, M., Yannone, S. M., Tainer, J. A., Campisi, J., Cooper, P. K. 2011; 10 (12): 1998-2007


    XPG is a structure-specific endonuclease required for nucleotide excision repair (NER). XPG incision defects result in the cancer-prone syndrome xeroderma pigmentosum, whereas truncating mutations of XPG cause the severe postnatal progeroid developmental disorder Cockayne syndrome. We show that XPG interacts directly with WRN protein, which is defective in the premature aging disorder Werner syndrome, and that the two proteins undergo similar subnuclear redistribution in S phase and colocalize in nuclear foci. The co-localization was observed in mid- to late S phase, when WRN moves from nucleoli to nuclear foci that have been shown to contain both protein markers of stalled replication forks and telomeric proteins. We mapped the interaction between XPG and WRN to the C-terminal domains of each, and show that interaction with the C-terminal domain of XPG strongly stimulates WRN helicase activity. WRN also possesses a competing DNA single-strand annealing activity that, combined with unwinding, has been shown to coordinate regression of model replication forks to form Holliday junction/chicken foot intermediate structures. We tested whether XPG stimulated WRN annealing activity, and found that XPG itself has intrinsic strand annealing activity that requires the unstructured R- and C-terminal domains but not the conserved catalytic core or endonuclease activity. Annealing by XPG is cooperative, rather than additive, with WRN annealing. Taken together, our results suggest a novel function for XPG in S phase that is, at least in part, performed coordinately with WRN, and which may contribute to the severity of the phenotypes that occur upon loss of XPG.

    View details for DOI 10.4161/cc.10.12.15878

    View details for Web of Science ID 000291651300026

    View details for PubMedID 21558802

  • VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKC delta-driven migration PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Razorenova, O. V., Finger, E. C., Colavitti, R., Chernikova, S. B., Boiko, A. D., Chan, C. K., Krieg, A., Bedogni, B., LaGory, E., Weissman, I. L., Broome-Powell, M., Giaccia, A. J. 2011; 108 (5): 1931-1936


    A common genetic mutation found in clear cell renal cell carcinoma (CC-RCC) is the loss of the von Hippel-Lindau (VHL) gene, which results in stabilization of hypoxia-inducible factors (HIFs), and contributes to cancer progression and metastasis. CUB-domain-containing protein 1 (CDCP1) was shown to promote metastasis in scirrhous and lung adenocarcinomas as well as in prostate cancer. In this study, we established a molecular mechanism linking VHL loss to induction of the CDCP1 gene through the HIF-1/2 pathway in renal cancer. Also, we report that Fyn, which forms a complex with CDCP1 and mediates its signaling to PKCδ, is a HIF-1 target gene. Mechanistically, we found that CDCP1 specifically regulates phosphorylation of PKCδ, but not of focal adhesion kinase or Crk-associated substrate. Signal transduction from CDCP1 to PKCδ leads to its activation, increasing migration of CC-RCC. Furthermore, patient survival can be stratified by CDCP1 expression at the cell surface of the tumor. Taken together, our data indicates that CDCP1 protein might serve as a therapeutic target for CC-RCC.

    View details for DOI 10.1073/pnas.1011777108

    View details for PubMedID 21233420

  • Deficiency in Bre1 Impairs Homologous Recombination Repair and Cell Cycle Checkpoint Response to Radiation Damage in Mammalian Cells RADIATION RESEARCH Chernikova, S. B., Dorth, J. A., Razorenova, O. V., Game, J. C., Brown, J. M. 2010; 174 (5): 558-565


    The pathway involving Bre1-dependent monoubiquitination of histone H2B lysine 123, which leads to Dot1-dependent methylation of histone H3 lysine 79 (H3K79me2), has been implicated in survival after exposure to ionizing radiation in Saccharomyces cerevisiae. We found that depletion of mammalian homologs of Bre1 compromises the response to ionizing radiation, leading to increased radiosensitivity and a G(2)/M checkpoint defect. The deficiency in Bre1a/b function was also associated with increased sensitivity to crosslinking drugs and defective formation of Rad51 foci in mouse cells, suggesting a defect in homologous recombinational repair analogous to that seen in Saccharomyces. In budding yeast, H3K79me2 is important for the recruitment of the checkpoint signaling protein Rad9 to sites of double-strand breaks (DSBs). However, in mammalian cells, 53BP1 (the Rad9 ortholog) in addition to H3K79me2 recognizes a different residue, H4K20me2, and some studies argue that it is H4K20me2 and not H3K79me2 that is the preferred target for 53BP1. We show here that depletion of Bre1b specifically reduced dimethylation of H3K79 without affecting dimethylation of H4K20. Thus our data suggest that the observed defects in the radiation response of Bre1a/b-deficient cells are associated with reduced H3K79me2 and not with H4K20me2.

    View details for DOI 10.1667/RR2184.1

    View details for Web of Science ID 000283829800003

    View details for PubMedID 20738173

    View details for PubMedCentralID PMC2988074

  • Roles of DNA repair and reductase activity in the cytotoxicity of the hypoxia-activated dinitrobenzamide mustard PR-104A MOLECULAR CANCER THERAPEUTICS Gu, Y., Patterson, A. V., Atwell, G. J., Chernikova, S. B., Brown, J. M., Thompson, L. H., Wilson, W. R. 2009; 8 (6): 1714-1723


    PR-104 is a dinitrobenzamide mustard currently in clinical trial as a hypoxia-activated prodrug. Its major metabolite, PR-104A, is metabolized to the corresponding hydroxylamine (PR-104H) and amine (PR-104M), resulting in activation of the nitrogen mustard moiety. We characterize DNA damage responsible for cytotoxicity of PR-104A by comparing sensitivity of repair-defective hamster Chinese hamster ovary cell lines with their repair-competent counterparts. PR-104H showed a repair profile similar to the reference DNA cross-linking agents chlorambucil and mitomycin C, with marked hypersensitivity of XPF(-/-), ERCC1(-/-), and Rad51D(-/-) cells but not of XPD(-/-) or DNA-PK(CS)(-/-) cells. This pattern confirmed the expected dependence on the ERCC1-XPF endonuclease, implicated in unhooking DNA interstrand cross-links at blocked replication forks, and homologous recombination repair (HRR) in restarting collapsed forks. However, even under anoxia, the hypersensitivity of XPF(-/-), ERCC1(-/-), and Rad51D(-/-) cells to PR-104A itself was lower than for chlorambucil. To test whether this reflects inefficient PR-104A reduction, a soluble form of human NADPH:cytochrome P450 oxidoreductase was stably expressed in Rad51D(-/-) cells and their HRR-restored counterpart. This expression increased hypoxic metabolism of PR-104A to PR-104H and PR-104M as well as hypoxia-selective cytotoxicity of PR-104A and its dependence on HRR. We conclude that PR-104A cytotoxicity is primarily due to DNA interstrand cross-linking by its reduced metabolites, although under conditions of inefficient PR-104A reduction (low reductase expression or aerobic cells), a second mechanism contributes to cell killing. This study shows that hypoxia, reductase activity, and DNA interstrand cross-link repair proficiency are key variables that interact to determine PR-104A sensitivity.

    View details for DOI 10.1158/1535-7163.MCT-08-1209

    View details for Web of Science ID 000267043100032

    View details for PubMedID 19509245

  • The role of RAD6 in recombinational repair, checkpoints and meiosis via histone modification DNA REPAIR Game, J. C., Chernikova, S. B. 2009; 8 (4): 470-482


    The Rad6 ubiquitin-conjugating enzyme in Saccharomyces cerevisiae is known to interact with three separate ubiquitin ligase proteins (Ubr1, Rad18, and Bre1) specific to different targets. The Rad6/Rad18 complex is central to translesion synthesis and the family of DNA transactions known as post-replication repair (PRR). A less well-known aspect of Rad6-mediated DNA repair, however, involves its function with Bre1 in mono-ubiquitinating the histone H2B residue lysine 123. Here, we review how this ubiquitination impacts histone H3 methylation, and how this in turn impacts the DNA damage response. In S. cerevisiae this pathway is required for checkpoint activation in G1, and contributes to DNA repair via the homologous recombination pathway (HRR) in G2 cells. Thus, RAD6 clearly plays a role in HRR in addition to its central role in PRR. We also summarize what is known about related repair pathways in other eukaryotes, including mammals. Recent literature emphasizes the role of methylated histones in S. cerevisiae, Schizosaccharomyces pombe and mammals in attracting the related DNA damage checkpoint proteins Rad9, Crb2 and 53BP1, respectively, to chromatin at the sites of DNA double-strand breaks. However, the specific histone modification pathways involved diverge in these different eukaryotes.

    View details for DOI 10.1016/j.dnarep.2009.01.007

    View details for Web of Science ID 000265470800007

    View details for PubMedID 19230796

  • Homologous recombination is the principal pathway for the repair of DNA damage induced by tirapazamine in mammalian cells CANCER RESEARCH Evans, J. W., Chernikova, S. B., Kachnic, L. A., Banath, J. P., Sordet, O., Delahoussaye, Y. M., Treszezamsky, A., Chon, B. H., Feng, Z., Gu, Y., Wilson, W. R., Pommier, Y., Olive, P. L., Powell, S. N., Brown, J. M. 2008; 68 (1): 257-265


    Tirapazamine (3-amino-1,2,4-benzotriazine-1,4-dioxide) is a promising hypoxia-selective cytotoxin that has shown significant activity in advanced clinical trials in combination with radiotherapy and cisplatin. The current study aimed to advance our understanding of tirapazamine-induced lesions and the pathways involved in their repair. We show that homologous recombination plays a critical role in repair of tirapazamine-induced damage because cells defective in homologous recombination proteins XRCC2, XRCC3, Rad51D, BRCA1, or BRCA2 are particularly sensitive to tirapazamine. Consistent with the involvement of homologous recombination repair, we observed extensive sister chromatid exchanges after treatment with tirapazamine. We also show that the nonhomologous end-joining pathway, which predominantly deals with frank double-strand breaks (DSB), is not involved in the repair of tirapazamine-induced DSBs. In addition, we show that tirapazamine preferentially kills mutants both with defects in XPF/ERCC1 (but not in other nucleotide excision repair factors) and with defects in base excision repair. Tirapazamine also induces DNA-protein cross-links, which include stable DNA-topoisomerase I cleavable complexes. We further show that gamma H2AX, an indicator of DNA DSBs, is induced preferentially in cells in the S phase of the cell cycle. These observations lead us to an overall model of tirapazamine damage in which DNA single-strand breaks, base damage, and DNA-protein cross-links (including topoisomerase I and II cleavable complexes) produce stalling and collapse of replication forks, the resolution of which results in DSB intermediates, requiring homologous recombination and XPF/ERCC1 for their repair.

    View details for DOI 10.1158/0008-5472.CAN-06-4497

    View details for Web of Science ID 000252072100033

    View details for PubMedID 18172318

  • Cell cycle-dependent effects of wortmannin on radiation survival and mutation RADIATION RESEARCH Chernikova, S. B., Lindquist, K. L., Elkind, M. M. 2001; 155 (6): 826-831


    Wortmannin, a known radiation sensitizer, has been used in experiments with synchronized cells to compare its effect on radiation survival and mutation induction within the cell cycle. PL61 cells (CHO cells with an inactivated HPRT gene containing a single active copy of a bacterial gpt gene) were synchronized by mitotic selection. Wortmannin administered before gamma irradiation caused a greater sensitization in G(1)-phase cells relative to late S/G(2)-phase cells. Preferential radiosensitization of G(1)-phase cells by wortmannin sets a limit to the proposed use of wortmannin in radiation therapy, since, in contrast to normal tissues, tumors usually have high proportions of S-phase cells. Wortmannin increased mutation frequencies in both G(1)- and S/G(2)-phase cells. Interestingly, relative increases in radiation-induced mutations in G(1) and S/G(2) phases were comparable. The results are discussed in terms of the contributions of different repair modes in the production of mutations.

    View details for Web of Science ID 000168991800009

    View details for PubMedID 11352765

  • Wortmannin sensitizes mammalian cells to radiation by inhibiting the DNA-dependent protein kinase-mediated rejoining of double-strand breaks RADIATION RESEARCH Chernikova, S. B., Wells, R. L., Elkind, M. M. 1999; 151 (2): 159-166


    Wortmannin has been shown to be an efficient radiosensitizer. Since wortmannin is able to inhibit DNA-dependent protein kinase (DNA-PK) and double-strand break (DSB) rejoining, it is believed that its mechanism of radiation sensitization is through the inhibition of DNA-PK-mediated repair of DSBs. However, since wortmannin is not a specific inhibitor, the possibility that other kinases are inhibited and thereby may contribute to radiosensitization cannot be ruled out. Here we present data confirming the radiosensitizing effect of wortmannin on cells of different cell lines. In the same range of wortmannin concentrations, survival after exposure to ionizing radiation correlated well with DSB rejoining and the induction of micronuclei, suggesting that the inhibition of the processing of DSBs is involved in the sensitizing effect. Pretreatment with wortmannin enhanced the radiosensitivity of ataxia telangiectasia (AT) cells, thereby precluding the participation of ATM protein in the radiation sensitization by wortmannin. At the same time, irradiated DNA-PK-deficient cells were not significantly affected by pretreatment with wortmannin. These observations support a likely mechanism; that is, wortmannin sensitizes cells to radiation through inhibition of the DNA-PK-mediated rejoining of DSBs.

    View details for Web of Science ID 000078720400006

    View details for PubMedID 9952300

  • [A comparison of the patterns of delayed cell death after exposure to genotoxic agents]. Tsitologiia Gotlib, V. I., SEREBRIANYI, A. M., Chernikova, S. B., Kudriashova, O. V., PELEVINA, I. I. 1996; 38 (9): 974-982


    A lot of data have been provided on different types of cells showing that ionizing radiation induces a hereditable genome instability, which may lead to mutations chromosome aberrations and cell death. In this paper we studied delayed death, proliferative activity, sensitivity to genotoxic agents to progeny of HeLa and LL cells following treatment with ionizing radiation, cis-platinum, methylhydroxurea which induce different types of lesions with different rate of repair. The rate of death of the progeny, dynamics of the clonogen ability recovery, growth rate recovery after the treatment with genotoxic agents are different. We have supposed that the delayed cell death may be associated with different types of hereditable lesions.

    View details for PubMedID 9019898

  • [Effect of low-dose ionizing radiation on radiosensitivity to the next irradiation]. Radiatsionnaia biologiia, radioecologiia / Rossiiskaia akademiia nauk Chernikova, S. B., Gotlib, V. I., PELEVINA, I. I. 1993; 33 (4): 537-541


    The action of low dose irradiation on the radiosensitivity of HeLa cells was studied. It was shown that preliminary irradiation of sells by dose of 3 cGy induces the adaptive response: decreasing of number of cells with micronuclei after posterior irradiation by doses of 2.0 and 3.0 Gy. The maximum level of the adaptive response is reached in 4 h and is observed in 3 cell cycles. When the dose of preliminary irradiation increases to 40 cGy the adaptive response is not observed, however the radiosensitivity of cells increases.

    View details for PubMedID 8401875

  • [The action of low doses of nitrosomethylurea on a stationary cell population. An experiment and modelling]. Izvestiia Akademii nauk SSSR. Seriia biologicheskaia Krutova, T. V., Chernikova, S. B., Konradov, A. A., Burlakova, E. B. 1992: 511-518


    The change of stationary cell population (murine spleen) following an exposure to low doses of methylnitrosourea (10(-11)-10(-5) g/kg of mouse weight) was investigated and modelled mathematically. The suggested model is based on the idea that the effect of cytotoxic agent in low doses has nondestructive "signal" character, changing dynamic balance between cells in proliferating and quiescent compartments.

    View details for PubMedID 1452900