Cells form the basis for all living organisms on earth. All genetic information needed for a cell to function properly within a living organism is stored within the DNA. The DNA of a cell is subject to various types of damage that can threaten its integrity, when not dealt with properly.
To protect genomic stability, cells have evolved an extensive signaling cascade that coordinates DNA repair during cell cycle progression. Activation of this DNA damage response results in checkpoint activation, which can halt the G1/S transition or the G2/M transition in the cell cycle. While spontaneous recovery after DNA damage is marked by the reversal of these checkpoints, cells can also irreversibly exit from the cycle and enter senescence or undergo apoptosis.
Previous studies have shown that the cellular fate following DNA damage can depend on the extent of damage or location of DNA lesions. Yet a mechanistic understanding of how cellular fate following a DNA damaging event is regulated in individual cells has been lacking.
In this thesis, Femke Feringa and het co-reseachers show that cell fate decisions are made differently when cells are damaged in G1 or in G2 phase. They found that cell fate is established within hours after DNA double strand break induction in G2 phase, while checkpoint reversibility is maintained substantially longer in G1 phase. Studying the relation between DNA repair and cellular fate, they discovered how the rapid cell fate decision in G2 phase can be determined by DNA repair efficiency. In addition, we find how incomplete DNA repair can also drive exit from the cell cycle in G2 phase when a cell encountered replication stress in S phase.
To their surprise, they fpund that DNA repair is no longer relevant for cellular fate when double strand breaks occur at the end of G2 phase in antephase. At this stage, the cell cycle conditions allow no other choice than to rapidly leave the cell cycle in order to protect genome stability.
Finally, the research group screened for genes that become specifically important for cell viability in the presence of DSBs. Using this approach, they identified several genes with a previously undescribed role in the DNA damage response, which opens up exciting opportunities for future studies.
Femke Feringa will defend her thesis at Utrecht University.
Title: Cell fate decisions after DNA damage. Withdraw the risky cases.
Promotor: prof.dr. René Medema
Date: Thursday, 29 March 2018
Read the notice about this PhD defense on the website of Utrecht University.