{"id":2244,"date":"2018-10-11T16:13:00","date_gmt":"2018-10-11T20:13:00","guid":{"rendered":"https:\/\/www.med.unc.edu\/vazirilab\/?page_id=2244"},"modified":"2018-10-31T15:06:34","modified_gmt":"2018-10-31T19:06:34","slug":"research","status":"publish","type":"page","link":"https:\/\/www.med.unc.edu\/vazirilab\/research\/","title":{"rendered":"Research"},"content":{"rendered":"

Some of our past work is summarized below:<\/strong><\/p>\n

    \n
  1. Regulation <\/b><\/u>of DNA Polymerase kappa (<\/b><\/u>Pol<\/b><\/u>k<\/b><\/u>)<\/b><\/u><\/li>\n<\/ol>\n

    Polk is a DNA damage-tolerant and error-prone DNA polymerase that sustains DNA synthesis on templates containing damage (for example bulky DNA adducts from environmental carcinogens such as the combustion product Benzo[a]pyrene).\u00a0 Our work helped define the activation mechanism of Polk which is dependent upon mono-ubiquitination of the replication fork component PCNA (Bi et al., Mol<\/i> Cell <\/i>Biol<\/i> 2004).<\/p>\n

    \"\"<\/p>\n

      \n
    1. Re-replication \u2013 a mechanism of genomic instability<\/b><\/u><\/li>\n<\/ol>\n

      To maintain genome stability cells must replicate their genomes only once every cell cycle.\u00a0 We discovered that imbalanced expression of DNA<\/p>\n

      replication licensing factors such as CDT1 and CDC6 leads to re-replication –\u00a0 an unusual process whereby origins of DNA replication are activated multiple times each S-phase.\u00a0 Re-replicating cells accumulate excess DNA and acquire DNA damage.\u00a0 The human tumor suppressor protein p53 prevents re-replication (Vaziri et al., Mol<\/i> Cell <\/i>2003).\u00a0 Interestingly, re-replication has also been proposed as a mechanism of oncogene-induced DNA damage.<\/p>\n

      \"\"<\/p>\n

        \n
      1. DNA <\/b><\/u>Polymerase kappa (Pol<\/b><\/u>k<\/b><\/u>) allows tolerance of oncogene-induced <\/b><\/u>DNA damage <\/b><\/u><\/li>\n<\/ol>\n

        Cancer\u00a0 cells experience high levels of DNA replication stress and DNA damage due to oncogene signaling.\u00a0 We found that Polk and its upstream activator RAD18 allow cells to tolerate oncogene-induced DNA damage (Yang et al., JCB <\/i>2017).\u00a0 Cells lacking Polk or RAD18 undergo fatal mitotic catastrophe in response to oncogene signaling.\u00a0 These results identify Polk and RAD18 as dependencies and molecular vulnerabilities of neoplastic cells.<\/p>\n

        \"\"<\/p>\n

          \n
        1. Cancer Testes Antigen (CTA)-mediated genome maintenance<\/b><\/u><\/li>\n<\/ol>\n

          Cancer Testes Antigens are germ cell-restricted proteins that are aberrantly expressed at high levels in many cancers.\u00a0 Increasingly it is suspected that CTAs confer tumorigenic phenotypes and contribute to carcinogenesis.\u00a0 Our proteomic screen for regulators of the TLS pathway identified Melanoma Antigen A4 (MAGE-A4, a CTA) as a novel RAD18-binding partner and activator (Gao et al., Nature Communications <\/i>2016).\u00a0 MAGE-A4-induced TLS provides a new mechanism for how neoplastic cells tolerate oncogenic and therapeutic DNA damage while simultaneously mutating their genomes via error-prone DNA replication.<\/p>\n

          \"\"<\/p>\n","protected":false},"excerpt":{"rendered":"

          Some of our past work is summarized below: Regulation of DNA Polymerase kappa (Polk) Polk is a DNA damage-tolerant and error-prone DNA polymerase that sustains DNA synthesis on templates containing damage (for example bulky DNA adducts from environmental carcinogens such as the combustion product Benzo[a]pyrene).\u00a0 Our work helped define the activation mechanism of Polk which … Read more<\/a><\/p>\n","protected":false},"author":28418,"featured_media":0,"parent":0,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_acf_changed":false,"footnotes":"","_links_to":"","_links_to_target":""},"class_list":["post-2244","page","type-page","status-publish","hentry","odd"],"acf":[],"yoast_head":"\nResearch - Vaziri Lab<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.med.unc.edu\/vazirilab\/research\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Research - Vaziri Lab\" \/>\n<meta property=\"og:description\" content=\"Some of our past work is summarized below: Regulation of DNA Polymerase kappa (Polk) Polk is a DNA damage-tolerant and error-prone DNA polymerase that sustains DNA synthesis on templates containing damage (for example bulky DNA adducts from environmental carcinogens such as the combustion product Benzo[a]pyrene).\u00a0 Our work helped define the activation mechanism of Polk which … Read more\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.med.unc.edu\/vazirilab\/research\/\" \/>\n<meta property=\"og:site_name\" content=\"Vaziri Lab\" \/>\n<meta property=\"article:modified_time\" content=\"2018-10-31T19:06:34+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/www.med.unc.edu\/vazirilab\/wp-content\/uploads\/sites\/648\/2018\/10\/Vaziri-Research-Image-1-300x80.png\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data1\" content=\"2 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\/\/schema.org\",\"@graph\":[{\"@type\":\"WebPage\",\"@id\":\"https:\/\/www.med.unc.edu\/vazirilab\/research\/\",\"url\":\"https:\/\/www.med.unc.edu\/vazirilab\/research\/\",\"name\":\"Research - 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