DNA damage response in skin, kidney and aging

In response to DNA damage, cells activate a complex signaling network to prevent further cell cycle progression. Activation of this signaling cascade, that is collectively referred to as the DNA damage response (DDR), provides time for DNA repair, recruits repair machinery to the sites of genotoxic damage, or, if the lesions are beyond repair capacity, leads to the activation of additional pathways mediating apoptosis.

Proliferative and postmitotic cells have different demands on the DNA damage response. Whereas proliferative tissues can tolerate apoptosis of a limited number of individual cells well and replace them quickly, postmitotic cells such as neurons and podocytes are keen to keep their integrity. Apoptosis Antagonizing Transcription Factor (Aatf/Che-1) is a central modulator of the DNA damage response. It inhibits p53-driven apoptosis and promotes cell cycle arrest after DNA damage. We use the genetic loss of Aatf to study the exact differences in the DNA damage response of various tissues that differ in their proliferative status. We use the epidermis as a model organ for proliferative tissue and study the quality of the DNA damage response in embryogenesis and after UV-light mediated damage. The kidney is a complex organ that consists of many different cell types. Two of them are of major interest in this project.

 

 
 
 
 
 

Podocytes are postmitotic cells of the kidney filter. Lost podocytes cannot be replaced. Progressive podocyte loss leads to proteinuria, renal scaring and end stage renal disease. Aged and diseased kidneys show progressive podocyte loss as well. The reason for this phenomenon is unclear. We suspect a weakened antagonism to the trigger of apoptosis due to accumulated DNA damage that results in podocyte loss in aging and diseased kidneys. We study the DNA damage response in podocytes via the knockout of different genes of the DNA damage response at different time points and disease settings.

Renal tubules are an equally fascinating cell type. In normal conditions, they do not divide. After loss of individual tubular cells, the neighbouring cells undergo mitosis and replace the gap. They are an excellent model to study the DNA damage response in tissue repair and maintenance. We here as well use genetic alterations of genes of the DNA damage response to influence the pathway. These models allow a broad and comprehensive analysis of the DNA damage response in vivo in different tissues and cell entities. They will help us decipher the pathogenesis of podocyte loss and tubular malrepair as well as the biology of epidermal malfunction.

Group leader

Dr. Katja Höpker

Teammembers

  • Martyna Brütting
  • Sadrija Cukoski
  • Manaswita Jain

 

Selected publications

  1. Desantis, A., Bruno, T., Catena, V., De Nicola, F., Goeman, F., Iezzi, S., Sorino, C., Gentileschi, M.P., Germoni, S., Monteleone, V., Pellegrino, M., Kann, M., De Meo, P.D., Pallocca, M., Hopker, K., Moretti, F., Mattei, E., Reinhardt, H.C., Floridi, A., Passananti, C., Benzing, T., Blandino, G., and Fanciulli, M. (2015). Che-1 modulates the decision between cell cycle arrest and apoptosis by its binding to p53. Cell Death Dis. 6: p. e1764.
  2. Liebau, M.C., Braun, F., Hopker, K., Weitbrecht, C., Bartels, V., Muller, R.U., Brodesser, S., Saleem, M.A., Benzing, T., Schermer, B., Cybulla, M., and Kurschat, C.E. (2013). Dysregulated autophagy contributes to podocyte damage in Fabry's disease. PLoS One. 8(5): p. e63506.
  3. Hopker, K., Hagmann, H., Khurshid, S., Chen, S., Hasskamp, P., Seeger-Nukpezah, T., Schilberg, K., Heukamp, L., Lamkemeyer, T., Sos, M.L., Thomas, R.K., Lowery, D., Roels, F., Fischer, M., Liebau, M.C., Resch, U., Kisner, T., Rother, F., Bartram, M.P., Muller, R.U., Fabretti, F., Kurschat, P., Schumacher, B., Gaestel, M., Medema, R.H., Yaffe, M.B., Schermer, B., Reinhardt, H.C., and Benzing, T. (2012). AATF/Che-1 acts as a phosphorylation-dependent molecular modulator to repress p53-driven apoptosis. EMBO J. 31(20): p. 3961-75.
  4. Hopker, K., Hagmann, H., Khurshid, S., Chen, S., Schermer, B., Benzing, T., and Reinhardt, H.C. (2012). Putting the brakes on p53-driven apoptosis. Cell Cycle. 11(22): p. 4122-8.
  5. Seeger-Nukpezah, T., Liebau, M.C., Hopker, K., Lamkemeyer, T., Benzing, T., Golemis, E.A., and Schermer, B. (2012). The centrosomal kinase Plk1 localizes to the transition zone of primary cilia and induces phosphorylation of nephrocystin-1. PLoS One. 7(6): p. e38838.