Genomic stability of pluripotent stem cells is crucial for its potential application in regenerative medicine. Compared to the somatic cells, pluripotent stem cells possess much stronger ability to maintain their genomic stability. However, the underlying molecular basis is far from clear. Filia is specifically and abundantly expressed in mouse growing oocytes and embryonic stem cells (ESCs). Two isoforms of Filia transcripts were generated through alternative splicing. The short isoform encodes protein of 346 amino acids and predominantly expressed in growing oocytes, whilst the long isoform encodes protein with 440 amino acids and expressed in ESCs. Genetic depletion of Filia from oocytes causes aneuploidy in cleavage-stage embryos. However, whether Filia displays similar role in governing genomic integrity of pluripotent stem cells was not investigated. In this work, we studied in detail the roles and the underlying molecular mechanism of Filia in maintaing the genomic stability of mouse ESCs. Our findings demonstrated that Filia was a master regulator of DNA damage response and played crucial roles in preserving genomic integrity of mouse ESCs. By utilizing the approaches of gene knockout, gene knockdown and gene rescue, we provided evidences supporting that Filia was essential to maintain genomic stability of mouse ESCs propagated in normal culture conditions. Upon loss of Filia protein, ESCs displayed various types of genomic instabilities, including aneuploidy, chromosome end-to-end fusion, increases in gama-H2A.X expression indicative of DNA double strand breaks. Moreover, Loss of Filia functions led to tumorigenic transformation of mouse ESCs. DNA damage response (DDR) is a fundamental and evolutionarily conserved mechanism to preserve genomic integrity of the cells. Upon DNA damage induced by endogenous or exogenous insults, cells elicit complicated but highly coordinated processes to recognize the damage, to generate, amplify and transduce the signalings to downstream effectors which in turn trigger multiple reactions including the cell cycle arrest, DNA repair machinery assembly or alternatively cell death if the damage fails to be repaired. Compared to somatic cells, ESCs display unique properties of DDR. For instance, mouse ESCs do not have G1/S cell cycle checkpoint due to the extremely short G1 phase.
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