Browsing by Author "Malkas, Linda H."

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Error-promoting DNA synthesis in ovarian cancer cells
    (Elsevier, 2013) Dai, Heqiao; Hickey, Robert J.; Liu, Jianying; Bigsby, Robert M.; Lanner, Carita; Malkas, Linda H.; Medicine, School of Medicine
    Objective: The objective of this study is to determine whether an altered DNA replication process is responsible for some of genetic damage observed in ovarian cancer. Methods: The replication fidelity of the DNA synthetic process was evaluated in both malignant and non-malignant human ovarian cells. The types of replication errors produced were identified. In addition, kinetic analyses of the efficiency of ovarian cancer DNA polymerases for misincorporating nucleotides were performed. Results: We report for the first time that ovarian cancer cells harbor an error promoting DNA replication apparatus which contributes to the decrease in DNA synthetic fidelity exhibited by these cells. Our study also shows that the decrease in DNA replication fidelity was not a result of an increased DNA replication activity. In addition, it was observed that the higher rate of DNA replication errors does not result in significant differences in the type of DNA replication-errors made during the DNA replication process; just the relative abundance. A detailed kinetic analysis of the efficiency of misincorporating nucleotides demonstrated that the DNA polymerases within the ovarian cancer cells exhibited a significant propensity for creating purine-pyrimidine nucleotide mismatches relative to non-malignant ovarian cells, while being only slightly more efficient at incorrectly pairing a purine nucleotide with a purine nucleotide. Conclusions: All together, these data suggest that the systematic analysis of the DNA replication process in ovarian cancer could uncover information on some of the molecular mechanisms that drive the accumulation of genetic damage, and probably contribute to the pathogenesis of the disease.
  • Thumbnail Image
    Item
    Human C6orf211 Encodes Armt1, a Protein Carboxyl Methyltransferase that Targets PCNA and Is Linked to the DNA Damage Response
    (ScienceDirect, 2015-03) Perry, J. Jefferson P.; Ballard, Gregory D.; Albert, Alexandra E.; Dobrolecki, Lacey E.; Malkas, Linda H.; Hoelz, Derek J.; Department of Hematology and Oncology, IU School of Medicine
    Recent evidence supports the presence of an L-glutamyl methyltransferase(s) in eukaryotic cells, but this enzyme class has been defined only in certain prokaryotic species. Here, we characterize the human C6orf211 gene product as “acidic residue methyltransferase-1” (Armt1), an enzyme that specifically targets proliferating cell nuclear antigen (PCNA) in breast cancer cells, predominately methylating glutamate side chains. Armt1 homologs share structural similarities with the SAM-dependent methyltransferases, and negative regulation of activity by automethylation indicates a means for cellular control. Notably, shRNA-based knockdown of Armt1 expression in two breast cancer cell lines altered survival in response to genotoxic stress. Increased sensitivity to UV, adriamycin, and MMS was observed in SK-Br-3 cells, while in contrast, increased resistance to these agents was observed in MCF7 cells. Together, these results lay the foundation for defining the mechanism by which this post-translational modification operates in the DNA damage response (DDR).
  • Thumbnail Image
    Item
    Indiana Breast Cancer Research Center
    (Office of the Vice Chancellor for Research, 2011-04-08) Malkas, Linda H.
    IUPUI is now positioned to take advantage of the breast cancer research related infrastructure that has been built on this campus over the last 9 years by establishing the Indiana Center for Breast Cancer Research. It is our intention to build on our unique research and clinical translational strengths to create a center of excellence dedicated to the prevention, early detection, and treatment of breast cancer. 16 basic and clinical investigators at IUPUI form the faculty of the Center. The charge of this Center is the rapid movement of laboratory discoveries into the clinic. To do this the Indiana Center for Breast Cancer Research seeks to understand the biology underlying breast cancer, to apply this understanding of breast cancer biology to improve prevention, diagnosis, and treatment, and to foster research that is interdisciplinary and translational in nature. To identify the molecular, biochemical and physical events that underlay the development and maintenance of breast cancer and to apply these findings to enhance the prevention, diagnosis and treatment of the disease requires a multidisciplinary approach encompassing basic and clinical science expertise. To facilitate this, the Director of this Center identified a very strong team of dedicated breast cancer investigators that span the clinical translation arena, and include: structural biology, gene expression, pathology, animal models, proteomics, genomics, biostatistics and bioinformatics. The research to be pursued by the Center faculty is conceptually linked in that each investigator is engaged in the study and discovery of breast cancer molecular phenotypes. The unique feature of this Center in the National breast cancer research field will be the novel molecular and therapeutic pathways and approaches pursued by the Center investigators. The breast cancer work to be carried out by the investigators will be exclusive to the Center and the first of its kind in the Nation. The spectrum of studies performed includes the development of novel agents, technologies, and markers for the better diagnosis, prognosis, screening, prevention, and treatment of breast cancer. Another overarching goal of the Center is that it serves as the starting and focal point for a planned application to the National Cancer Institute (NCI) to establish a Breast Cancer Specialized Program of Research Excellence (SPORE) here on the IUPUI campus. (There has never been a SPORE for any type of cancer at any of the IU campuses or within the State of Indiana). The Indiana Center for Breast Cancer Research will permit the growth of a sharply focused multidisciplinary program that will form the basis of the research and infrastructure required to successfully compete in the highly competitive process of securing a NCI SPORE for breast cancer. We estimate that establishment of the Indiana Center for Breast Cancer Research will permit us to submit a NCI SPORE application in the next 2 – 3 years.