title: Interconnected contribution of tissue morphogenesis and the nuclear protein NuMA to the DNA damage response.
abstract: Epithelial tissue morphogenesis is accompanied by the formation of a polarity axis--a feature of tissue architecture that is initiated by the binding of integrins to the basement membrane. Polarity plays a crucial role in tissue homeostasis, preserving differentiation, cell survival and resistance to chemotherapeutic drugs among others. An important aspect in the maintenance of tissue homeostasis is genome integrity. As normal tissues frequently experience DNA double-strand breaks (DSBs), we asked how tissue architecture might participate in the DNA damage response. Using 3D culture models that mimic mammary glandular morphogenesis and tumor formation, we show that DSB repair activity is higher in basally polarized tissues, regardless of the malignant status of cells, and is controlled by hemidesmosomal integrin signaling. In the absence of glandular morphogenesis, in 2D flat monolayer cultures, basal polarity does not affect DNA repair activity but enhances H2AX phosphorylation, an early chromatin response to DNA damage. The nuclear mitotic apparatus protein 1 (NuMA), which controls breast glandular morphogenesis by acting on the organization of chromatin, displays a polarity-dependent pattern and redistributes in the cell nucleus of basally polarized cells upon the induction of DSBs. This is shown using high-content analysis of nuclear morphometric descriptors. Furthermore, silencing NuMA impairs H2AX phosphorylation--thus, tissue polarity and NuMA cooperate to maintain genome integrity.
authors.affiliation: Department of Basic Medical Sciences, Purdue University, West Lafayette, IN 47907, USA. pvidi@purdue.edu
authors.forename: Pierre-Alexandre
authors.initials: PA
authors.lastname: Vidi
authors.forename: Gurushankar
authors.initials: G
authors.lastname: Chandramouly
authors.forename: Matthew
authors.initials: M
authors.lastname: Gray
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Er
authors.initials: E
authors.lastname: Liu
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Kim
authors.forename: Vassilis
authors.initials: V
authors.lastname: Roukos
authors.forename: Mina J
authors.initials: MJ
authors.lastname: Bissell
authors.forename: Prabhas V
authors.initials: PV
authors.lastname: Moghe
authors.forename: Sophie A
authors.initials: SA
authors.lastname: Lelièvre
mesh_terms: D061354:Acinar Cells / Q000378:metabolism; D034961:Antigens, Nuclear / Q000378:metabolism / Q000502:physiology*; D001485:Basement Membrane / Q000378:metabolism; D001940:Breast / Q000166:cytology; D018929:Cell Culture Techniques; D018797:Cell Cycle Proteins; D002460:Cell Line; D045744:Cell Line, Tumor; D016764:Cell Polarity; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004847:Epithelial Cells; D004848:Epithelium / Q000254:growth & development; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D009024:Morphogenesis; D034521:Nuclear Matrix-Associated Proteins / Q000378:metabolism / Q000502:physiology*
chemical_list: D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; D006657:Histones; C050045:NUMA1 protein, human; D034521:Nuclear Matrix-Associated Proteins