Genomes and Genes
Homeostatic Roles of Connexin43 in Response to DNA Damage
Principal Investigator: DANNY SAM ROH
Abstract: DESCRIPTION (provided by applicant): DNA damage can significantly alter cell function and viability, thus, the accumulation of unrepaired DNA damage is believed to be a major influence in the deterioration of organ function in aging. However, cells also respond to DNA damage in many other ways beyond DNA repair in order to maintain their function and viability. In particular, genes involved in intercellular communication, such as connexins, have been identified as key components in cellular responses to numerous stressors. Despite this, the molecular mechanisms by which intercellular communication is modified after genotoxic stress have not been described. The overall goal of this F30 proposal is to understand the responses to DNA damage in corneal endothelial (CE) cells whose pump and barrier functions are essential for corneal transparency and which in vivo display age-related degeneration and accumulation of DNA damage. Using an in vitro model of CE cells, we have recently observed significant changes in the gap junction protein connexin-43 (Cx43) after exposure to DNA damage-inducing agents. To explain the cellular mechanism(s) behind these changes, we consider a potential link between DNA damage and cell communication via casein kinase-1 delta (CK1?), which is both activated by DNA damage and an essential Cx43 kinase. Our overall hypothesis is that a protective cellular response to DNA damage involves stabilization of gap junction intercellular communication which is (a) mediated by changes in Cx43 expression and site-specific phosphorylation by CK1?), and (b) required for maintenance of viability and function. This will be tested with two specific aims that will determine 1) the mechanism(s) by which DNA damage mediates modification of connexin-43 (Cx43) and 2) the physiological consequence(s) of these changes during DNA damage including effects of CE cell viability and function. The results of this project will further our understanding of stress responses to DNA damage and provide insights into how the viability of certain aging tissues may be potentially enhanced. The aging process in which the body's cells, tissues, and organs progressively deteriorate has been associated with the accumulation of DNA damage. In response to such stress, a cell may survive or perish depending on its ability to cope with that damage. This proposal studies a potential coping mechanism to DNA damage that involves changes in how damaged cells communicate with one another to maintain their function and viability.
Funding Period: 2010-03-01 - 2013-05-31
more information: NIH RePORT
- Rapid changes in connexin-43 in response to genotoxic stress stabilize cell-cell communication in corneal endotheliumDanny S Roh
Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
Invest Ophthalmol Vis Sci 52:5174-82. 2011..To determine how corneal endothelial (CE) cells respond to acute genotoxic stress through changes in connexin-43 (Cx43) and gap junction intercellular communication (GJIC)...
- Age-related dystrophic changes in corneal endothelium from DNA repair-deficient miceDanny S Roh
Department of Ophthalmology, University of Pittsburgh School of Medicine, 203 Lothrop St, Pittsburgh, PA 15213, USA
Aging Cell 12:1122-31. 2013..These data provide strong experimental evidence that DNA damage can promote aging of the CE and that Ercc1(-/Δ) mice offer a rapid and accurate model to study CE pathogenesis and therapy. ..
- Gap junctions in Vascular Smooth Muscle: growth controlJanis M Burt; Fiscal Year: 2013..abstract_text> ..
- Internalization of gap junctions as a regulatory mechanism of direct GJICMatthias M Falk; Fiscal Year: 2013....