Genomic Integrity Safeguards Self-Renewal in Embryonic Stem Cells

A multitude of signals are coordinated to maintain self-renewal in embryonic stem cells (ESCs). To unravel the essential internal and external signals required for sustaining the ESC state, we expand upon a set of ESC pluripotency-associated phosphoregulators (PRs) identified previously by short hairpin RNA (shRNA) screening. In addition to the previously described Aurka, we identify 4 additional PRs (Bub1b, Chek1, Ppm1g, and Ppp2r1b) whose depletion compromises self-renewal and leads to consequent differentiation. Global gene expression profiling and computational analyses reveal that knockdown of the 5 PRs leads to DNA damage/genome instability, activating p53 and culminating in ESC differentiation. Similarly, depletion of genome integrity-associated genes involved in DNA replication and checkpoint, mRNA processing, and Charcot-Marie-Tooth disease lead to compromise of ESC self-renewal via an increase in p53 activity. Our studies demonstrate an essential link between genomic integrity and developmental cell fate regulation in ESCs. [Display omitted] •Five phosphoregulators (PRs) are essential for ESC identity•Depletion of the 5 PRs leads to activation of p53 and accumulation of DNA damage•Depletion of genome maintenance-associated genes compromises ESC self-renewal•Maintaining genome stability is required for ESC self-renewal Su et al. integrate system analyses with functional genomics screening to identify five phosphoregulators (PRs) that are indispensable for ESC self-renewal. Loss of genome stability control pathways impairs ESC self-renewal, activates p53, and promotes ESC differentiation. These findings suggest that maintenance of genome integrity is essential for ESC self-renewal.