Journal
JOURNAL OF CELL SCIENCE
Volume 125, Issue 2, Pages 350-361Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.089177
Keywords
Tissue architecture; Basal polarity; Nuclear mitotic apparatus protein; DNA double-strand break; Chromatin; Three-dimensional cell culture
Categories
Funding
- National Institutes of Health [R01CA112017, P41EB001046]
- Bay Area Physical Sciences-Oncology Center, University of California, Berkeley, California [R37CA064786, U54CA126552, R01CA057621, U54CA112970, U01CA143233, U54CA143836]
- U.S. Department of Energy, Office of Biological and Environmental Research and Low Dose Radiation [DE-AC02-05CH1123]
- US Department of Defense [W81XWH0810736]
- Novartis Foundation
- Swiss National Science Foundation [PBNEA-116967]
- NIH
- National Cancer Institute
- Purdue University Center for Cancer Research
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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.
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