The stability of our genome is constantly threatened by endogenous and exogenous processes causing errors in the DNA. Those have to be repaired as otherwise mutations can give rise to disease or tumor development. This is accomplished by various ways of DNA damage signaling and repair. One of the main proteins involved in the signaling and repair of DNA double strand breaks is Nbrin (NBN). A mutation of this protein is known to cause Nijmegen breakage syndrome (NBS) (Varon et al.,1998). Patients with NBS present with various clinical conditions e.g. microcephaly, immunodeficiency, radio sensitivity and a predisposition for tumor development (Varon et al.,1998; Cybulski et al.,2004; Assaf et al.,2008; Bogdanova et al.,2008; Huang et al.,2008; Watanabe et al.,2009). NBS patients show different skin malignancies as abnormal pigmentation, Porokeratosis and thin and sparse hair (van der Burgt et al.,1996; Group,2000; Wolf and Shwayder,2009; Chrzanowska et al.,2012). Mutations of NBN were discovered in malignant melanoma (Debniak et al.,2003; Thirumaran et al.,2006; Meyer et al.,2007). As the skin is our protection against environmental threats and undergoes a continuous self-renewal, the repair of DNA damages is crucial. The skin malignancies of NBS patients point toward an involvement of NBN in the DNA damage signaling and repair in the skin. A mouse model of Nbn deletion after birth in the epidermis and hair follicles was created to investigate Nbn function in the skin. The NbnKrox20-Cre mice exhibited a hair loss starting with the first wave of hair follicle growth (anagen phase) after birth. The hair loss was due to an increase of DNA damages and a failure in repair of those. Apoptosis rate was elevated and epidermal stem cell properties were disrupted. The hair follicles were not able to regenerate. Additionally, a thickening of the epidermis was detected in Nbn deleted mice with 3 months of age. Analyses revealed that the mice exhibited a psoriasis-like phenotype. An enlargement of the epidermis, invasion of immune cells, activation and expression changes of psoriasis typical markers were observed. Combined inactivation with p53 led to a worsening of the phenotype of the mice. Precancerous lesions were present. These findings show the importance of Nbn in skin and hair follicle homeostasis and in the prevention of skin cancer and psoriasis. The role of Atm (Ataxia telangiectasia mutated) in combination with Nbn in the skin was also investigated using a deletion mouse model. The influence of Atm on Nbn was found to depend on the cell type. In keratinocytes only a minor role of Atm was detected. However, Atm played an important role in hair follicle cells, where it was needed for the phosphorylation of Histone H2A.X. The role of Atm in combination with Nbn in proliferating tissue was shown by this.
Loss of Nbn activity in mice leads to the loss of hair follicle stem cells which causes hair loss and an increased proliferation of the basal keratinocytes gives rise to a psoriasis-like phenotype.
|Supervisor:||von Kalle, Prof. Dr. Christof|
|Date of thesis defense:||10 July 2014|
|Date Deposited:||29 Jul 2014 07:19|
|Faculties / Institutes:||The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences|
|Subjects:||570 Life sciences|