Ronin influences the DNA damage response in pluripotent stem cells

- Ronin binds to nucleotide excision repair and DNA damage genes that are downregulated upon Ronin loss.
- Ronin-knockout sensitizes embryonic stem cells to ionizing and UV-C irradiation.
- Atr-dependent DNA damage checkpoint activation is increased in Ronin-knockout cells after DNA damage.
- Ronin-knockout cells show increased G2/M arrest after DNA damage.

Early mammalian embryonic cells must maintain a particularly robust DNA repair system, as mutations at this developmental point have detrimental consequences for the organism. How the repair system can be tuned to fulfill such elevated requirements is largely unknown, but it may involve transcriptional regulation. Ronin (Thap11) is a transcriptional regulator responsible for vital programs in pluripotent cells. Here, we report that this protein also modulates the DNA damage response of such cells. We show that conditional Ronin knockout sensitizes embryonic stem cells (ESCs) to UV-C-induced DNA damage in association with Atr pathway activation and G2/M arrest. Ronin binds to and regulates the genes encoding several DNA repair factors, including Gtf2h4 and Rad18, providing a potential mechanism for this phenotype. Our results suggest that the unique DNA repair requirements of the early embryo are not met by a static system, but rather via highly regulated processes.