Regulation of DNA end resection by cell stemness
|Checa Rodríguez, Cintia
|Huertas Sánchez, Pablo
|Universidad de Sevilla. Departamento de Genética
|The ability to reprogram somatic cells into induced pluripotent stem cells (iPSCs) holds great potential for clinic applications, however, acquired genomic instability is one of the major concerns for its clinical use. The ...
The ability to reprogram somatic cells into induced pluripotent stem cells (iPSCs) holds great potential for clinic applications, however, acquired genomic instability is one of the major concerns for its clinical use. The reprogramming process is accompanied by the induction of DNA damage, of which double-strand breaks (DSBs) are the most cytotoxic. To minimize the impact of these damages, cells have developed two main repair pathways: Homologous Recombination (HR) and Non-Homologous End-Joining (NHEJ). The choice between both mechanisms is a complex and highly regulated process and the right balance is critical to ensure the maintenance of genomic stability. One of the best-known decision points is DNA end resection which leads to HR activation, and the nuclear protein CtIP is its major regulator. In this thesis, we investigated the role of DNA end resection and CtIP during the reprogramming process and we revealed that reprogramming is associated with high CtIP protein levels and a hyper-activation of DNA end resection. Moreover, CtIP is essential for the maintenance of genomic stability and reprogramming in a resection-defective environment has long-term consequences on stem cell self-renewal and differentiation. Furthermore, we show that the pluripotency factor KLF4 plays an important role in regulating DNA damage repair processes and the balance between them acting upon the HR pathway, specifically promoting DNA-end resection.
|Checa Rodríguez, C. (2020). Regulation of DNA end resection by cell stemness. (Tesis Doctoral Inédita). Universidad de Sevilla, Sevilla.