Abstract
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.
Highlights
The pluripotent stem cell state is maintained by a core set of transcription factors (e.g., Oct4, Sox2, and Nanog) that activate self-renewal genes and suppress lineage-specific differentiation pathways (Dejosez and Zwaka, 2012; Ng and Surani, 2011)
We show that Ronin regulates genes involved in the response to UV-C irradiation, and that conditional Ronin knockout increases the sensitivity of embryonic stem cells (ESCs) to DNA damage and activates the Atr-mediated DNA damage response
We found that genes belonging to the gene ontology (GO) categories for “response to DNA damage stimulus” (GO: 0006974) were enriched for the binding of Ronin (P=0.0009) and Oct4 (P=0.003) (Fig. 1A)
Summary
The pluripotent stem cell state is maintained by a core set of transcription factors (e.g., Oct, Sox, and Nanog) that activate self-renewal genes and suppress lineage-specific differentiation pathways (Dejosez and Zwaka, 2012; Ng and Surani, 2011). A second class of transcription factors helps maintain pluripotency by controlling general cell-vital programs that are critical for the rapid growth of pluripotent stem cells (Smith et al, 2011; Dejosez et al, 2010; Dejosez and Zwaka, 2012). Along with lineage-specific transcription factors like Oct and Sox, Ronin helps to maintain the uniquely robust genomic integrity of pluripotent stem cells
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