The funktionality of DNA damage response pathmays in mammalian somatic stem cells and their role in oncogenic transformation, survival and differentiation
Zusammenfassung der Projektergebnisse
By studying the DNA damage responses in neural stem cells (NSC) and their terminally differentiated descendants we could provide novel insights in their specific physiology and the related gene expression and signaling patterns. The initial objective of addressing the functionality of DNA damage response (DDR) signaling pathways has led to several striking discoveries: - While NSC show the canonical activation of DDR after irradiation, terminally differentiated astrocytes transcriptionally downregulate the DDR genes. Hence, in irradiated astrocytes H2AX is phosphorylated non-canonically by the kinase DNA-PK and not ATM. - Irradiation of self-renewing NSC leads to their exit form cell cycle and cellular senescence, which we show to involve secretion of active cytokines, corresponding to the model of senescence-associated secretory phenotype (SASP) discovered in fibroblasts. - Secreted cytokine BMP2 is required for the induction of astrocytic differentiation of irradiated and senescent NSC, which thus happens cell-autologously and independently of extrinsic cues. - DDR factors play a significant mechanistic role as SASP and the dependent astrocytic differentiation were stimulated by ATM and opposed by p53. - BMP2 was shown to signal in irradiated NSC predominantly through JAK-STAT in a novel non-canonical fashion to induce astrocytic differentiation. We could recapitulate the observations of DNA damage induced differentiation of NSC in vivo using a special mouse model of cell fate tracing. Moreover, we discovered that also glioblastoma (GBM) stem cells lose their tumorigenicity and undergo astrocytic differentiation after irradiation. In a side project, we addressed other types of stress to NSC and uncovered that DNA substitution with halogenated nucleotide BrdU lead to DNA demethylation and the ensuing astrocytic differentiation of BrdU exposed NSC. Summarizing, the project revealed a novel phenotype of DNA damage induced differentiation in NSC and elucidated its mechanism. The data offers new insights and perspectives for understanding of tissue homeostasis and ageing, which depend on the functionality of the somatic stem cells. Importantly, based on these data, an Emmy Noether grant proposal to study genotoxic and non-genotoxic stress responses in NSC has been recently submitted.
Projektbezogene Publikationen (Auswahl)
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“Terminally differentiated astrocytes lack DNA damage response signaling and are radioresistant but retain DNA repair proficiency”. Cell Death and Differentiation 2011 Apr;19(4):582-91
Schneider L., Fumagalli M., d’Adda di Fagagna F.
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“Neural stem cells exposed to BrdU lose their global DNA methylation and undergo astrocytic differentiation”. Nucleic Acids Research 2012 Jul;40(12):5332-42
Schneider L., d’Adda di Fagagna F.
