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Wednesday, October 18th, 2017
Centre de Recherche - Orsay - Amphithéâtre du Bâtiment 111

Cell fate decisions after DNA damage

Activation of the DNA damage checkpoint can lead to the induction of a cell
cycle arrest at various stages in the cell cycle. This cell cycle arrest is
transient in nature if the damage is not too excessive. We find that checkpoint
reversibility in G2 phase critically depends on Emi1 and is lost in prophase
cells. DNA damage in a prophase cell leads to rapid degradation of Cyclin B1
and the induction of senescence, even at low levels of DNA damage.
Importantly, while inhibition of Emi1 renders the checkpoint irreversible
throughout G2, restoration of checkpoint reversibility in prophase promotes
cell division with residual damage. Thus, reversibility of the DNA damage
checkpoint at low levels of DNA damage in G2 depends on Emi1, and is lost
in prophase cells to protect genomic integrity.
The situation is different when cells sustain high levels of DNA damage.
Under these conditions, the checkpoint response can also become
irreversible in G2 cells, whilst maintaining a reversible character in G1. We
find that the decision to irreversibly withdraw from the cell cycle is made within
a few hours following damage in G2 cells. We demonstrate that a permanent
arrest is dependent on induction of p53 and p21, resulting in the nuclear
translocation of Cyclin B1. This rapid response is followed by the activation of
the APC/CCdh1 several hours later. Inhibition of APC/CCdh1 activity fails to
prevent cell cycle withdrawal. In contrast, preventing nuclear retention of
Cyclin B1 does allow cells to remain in cycle. Importantly, transient induction
of p53 in G2 cells is sufficient to induce senescence. Taken together, these
results indicate that a rapid and transient pulse of p53 in G2 can drive nuclear
translocation of Cyclin B1 as the first irreversible step in the onset of


René H. Medema

Netherlands Cancer Institute, Amsterdam, The Netherlands

Invited by

Aura Carreira
Domain 1 - UMR 3348 - Genotoxic Stress and Cancer

Institut Curie


Aura Carreira

Institut Curie

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