To decipher DNA double strand break repair pathways during mitosis – MitoticRepair
To mitigate the threat of DNA double strand breaks (DSBs), human cells rely on the activity of multiple DNA repair machineries, that are tightly regulated throughout the cell cycle. In interphase, DSBs are mainly repaired by non-homologous end joining (NHEJ) and homologous recombination (HR). However, these pathways are completely inhibited in mitosis to prevent chromosomal rearrangements. The fate of mitotic DSBs remained unknown until our recent study showed that DNA polymerase theta (Pol?) repairs mitotic DSBs. In contrast to other repair factors, we found that Pol? is activated in mitosis upon phosphorylation. Phosphorylated Pol? is recruited by TopBP1 to mitotic DSBs, where it mediates joining of broken DNA ends and thereby maintains genome integrity. Our findings highlight the importance of understanding mitotic repair.
Despite these advances, little is known about the composition, regulation and mode of action of Pol? in mitosis. Furthermore, we speculate that additional, Pol?-independent, mitotic repair pathways remain to be discovered. Our working hypothesis is that TopBP1 serves as a recruitment platform to regulate crosstalks between the different mitotic repair pathways. We further postulate that, in the Pol? pathway, phospho-dependent interactions between Pol? and its partner proteins, including TopBP1, play a central role. Our goal is to study in depth mitotic repair to identify new genome stability maintenance mechanisms. Our project relies on teams with complementary strengths in structure analysis, biochemistry and tumor biology, in order to combine approaches of (opto)genetics, mass spectrometry, NMR, crystallography, in vitro and in-cell microscopies.
Project coordination
Raphael CECCALDI (Cancer, Heterogeneity, Instability and Plasticity, U830)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Partner
IGH Institut de Génétique Humaine
CHIP Cancer, Heterogeneity, Instability and Plasticity, U830
I2BC Institut de Biologie Intégrative de la Cellule
Help of the ANR 620,407 euros
Beginning and duration of the scientific project:
December 2023
- 36 Months