Role of dyskerin in oral epithelial homeostasis

Summary

Principal Investigator: Faizan Alawi
Abstract: DESCRIPTION (provided by applicant): The candidate has dedicated himself to a career in oral health-related research to complement his training in oral and maxillofacial pathology. He is applying for a K08 Mentored Clinical Scientist Development Award to facilitate protected time for the pursuit of his research activities together with didactic training in Translational Research methodology. During the course of the award period, he will obtain formal instruction, acquire new skills, learn cutting-edge methodologies, and directly benefit from the guidance and expertise of world-class investigators. Under the outstanding mentorship of Drs. Anil Rustgi and Sarah Millar, and the experience and insights of a diverse Advisory Committee, the Career Development Award will ensure that Dr. Alawi can continue his professional development and achieve his goal of becoming an independent investigator. Oral squamous epithelial cells undergo a well-defined differentiation program. To that end, several genetic diseases, including X-linked dyskeratosis congenita (DC), affect the oral mucosal tissues. X-linked DC is caused by mutations in the DKC1 (dyskerin) gene. Oral leukoplakia is one of the most common clinical manifestations, and the appearance of these preneoplastic lesions during childhood and adolescence indicates that loss of normal dyskerin function disrupts oral epithelial homeostasis. However, the mechanisms remain to be elucidated. Dyskerin is required for the biogenesis of ribonucleoproteins that incorporate small non-coding RNA molecules characterized by the H/ACA secondary structure. It is in this capacity that dyskerin contributes to telomerase activity and precursor rRNA processing. However, while both of these cellular processes are repressed during mitosis, we have shown that dyskerin expression peaks during mitosis, the protein localizes to distinct sub-cellular structures in mitotic oral keratinocytes, and acute loss of dyskerin function triggers G2/M arrest and leads to the accumulation of atypical mitoses with multi-polar spindles. We also recently demonstrated that dyskerin depletion reduces the levels of a subset of H/ACA small nucleolar RNA-derived microRNAs (miRNA) and their corresponding precursors. MicroRNAs play critical roles in the maintenance of normal cell homeostasis through regulation of post-transcriptional gene expression, including of genes essential for mitosis. In this hypothesis-driven proposal, we will use novel morphological, biochemical, functional and genetic approaches to determine the mechanisms by which dyskerin and its cognate RNA critically regulate oral epithelial homeostasis. In particular, we will (1) determine the role and mechanism of dyskerin localization during mitosis, (2) determine the role of dyskerin in post-transcriptional gene expression and (3) determine the in vivo effects of dyskerin mutation on oral epithelium using a mouse model of X-linked DC. By elucidating novel functions for dyskerin, identifying the roles of its associated RNA, and by complementing in vitro experiments with in vivo investigations, these studies will lead to a wealth of new knowledge that may result in novel therapeutic strategies for oral leukoplakia and X-linked DC.
Funding Period: 2011-07-08 - 2016-06-30
more information: NIH RePORT

Top Publications

  1. pmc An update on granulomatous diseases of the oral tissues
    Faizan Alawi
    Department of Pathology, School of Dental Medicine, University of Pennsylvania, 240 South 40th Street, Room 328B, Philadelphia, PA 19104 6002, USA Electronic address
    Dent Clin North Am 57:657-71. 2013
  2. pmc Pigmented lesions of the oral cavity: an update
    Faizan Alawi
    Department of Pathology, School of Dental Medicine, University of Pennsylvania, 240 South 40th Street, Room 328B, Philadelphia, PA 19104 6002, USA Electronic address
    Dent Clin North Am 57:699-710. 2013
  3. pmc Dyskerin localizes to the mitotic apparatus and is required for orderly mitosis in human cells
    Faizan Alawi
    Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
    PLoS ONE 8:e80805. 2013
  4. pmc Acute dyskerin depletion triggers cellular senescence and renders osteosarcoma cells resistant to genotoxic stress-induced apoptosis
    Ping Lin
    Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
    Biochem Biophys Res Commun 446:1268-75. 2014

Detail Information

Publications4

  1. pmc An update on granulomatous diseases of the oral tissues
    Faizan Alawi
    Department of Pathology, School of Dental Medicine, University of Pennsylvania, 240 South 40th Street, Room 328B, Philadelphia, PA 19104 6002, USA Electronic address
    Dent Clin North Am 57:657-71. 2013
    ..This article highlights some of the current knowledge about the more common granulomatous systemic diseases that may be encountered in clinical practice. ..
  2. pmc Pigmented lesions of the oral cavity: an update
    Faizan Alawi
    Department of Pathology, School of Dental Medicine, University of Pennsylvania, 240 South 40th Street, Room 328B, Philadelphia, PA 19104 6002, USA Electronic address
    Dent Clin North Am 57:699-710. 2013
    ..Although biopsy is a helpful and necessary aid in the diagnosis of focally pigmented lesions, with diffuse presentations lesions require a thorough history and laboratory studies to establish a definitive diagnosis. ..
  3. pmc Dyskerin localizes to the mitotic apparatus and is required for orderly mitosis in human cells
    Faizan Alawi
    Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
    PLoS ONE 8:e80805. 2013
    ..Together, these findings suggest that dyskerin is a highly dynamic protein throughout the cell cycle and increases the repertoire of fundamental cellular processes that are disrupted by absence of its normal function. ..
  4. pmc Acute dyskerin depletion triggers cellular senescence and renders osteosarcoma cells resistant to genotoxic stress-induced apoptosis
    Ping Lin
    Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
    Biochem Biophys Res Commun 446:1268-75. 2014
    ..Since U2OS cells are telomerase-negative, this leads us to conclude that loss of dyskerin function can also induce cellular senescence via mechanisms independent of telomere shortening. ..

Research Grants30

  1. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  2. RNA Binding Proteins in Cancer
    Shrikant Anant; Fiscal Year: 2013
    ..abstract_text> ..
  3. Center for the Study of Reproductive Biology and Women's Health
    Jeffrey W Pollard; Fiscal Year: 2013
    ..He holds several senior administrative appointments in the College of Medicine and is well able to administer the proposed SCCPIR internally and to enable effective interactions with other SCCPIRs. ..
  4. Superfund Metal Mixtures, Biomarkers and Neurodevelopment
    David C Bellinger; Fiscal Year: 2013
    ..Aim 4- To promote rapid dissemination of significant research findings;and Aim 5- Compliance- To ensure compliance with NIH requirements for data and resource-sharing and the human and animal institutional review board requirements ..
  5. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  6. Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation
    Timothy J Mitchison; Fiscal Year: 2013
    ..In aim 4 we will pursue several approaches towards translating mechanistic understanding from aims 1-3 into improved patient care. ..
  7. COLD SPRING HARBOR LABORATORY CANCER RESEARCH CENTER
    Gregory J Hannon; Fiscal Year: 2013
    ..Finaily, the Program benefits from, and contributes to, the collaborative environment fostered by the Coid Spring Harbor Laboratory Cancer Center and is at the heart of its activities. ..