2, 4). Of note, loss of TRRAP was accompanied by a dramatic loss of both c-Myc and E2F1 binding at the

cycin A promoter (Fig. 5D-F), suggesting that TRRAP and/or HAT-mediated acetylation play an important role Dabrafenib price in the recruitment of these transcription factors to the cyclin promoters in regenerating livers. Our results demonstrate that TRRAP and HATs play a critical role in liver regeneration through their function in cell cycle reentry and proliferation of quiescent hepatocytes following liver damage. After CCl4treatment, TRRAP-deficient mice revealed impaired liver regeneration without alteration of the degree of initial histologic injury, indicating that TRRAP is needed for regeneration of damaged liver tissue. TRRAP-deficient hepatocytes exhibited a dramatic PD0332991 in vitro proliferation defect as seen by the dramatic reduction in both BrdU- and PCNA-positive cells in TRRAP-deficient livers after CCl4 treatment. These findings show that TRRAP is essential for cell cycle entry of hepatocytes after liver injury and that the reduced viability of TRRAP-deficient

mice treated with CCl4 may be caused by the hepatocytes’ failure to regenerate the injured liver. However, the possibility that loss of TRRAP may affect other liver functions, which may contribute to the phenotype of TRRAP-deficient mice, could not be formally ruled out. The observation that TRRAP-CKO livers after CCl4 treatment did show an increase in hepatocyte proliferation, although more severely attenuated than that seen in TRRAP-containing livers, may be explained by the presence of the remaining TRRAP protein in a fraction of the hepatocytes (“escapers of deletion”), which may be sufficient to support cell cycle entry. However, TRRAP protein levels may be further diluted during cell cycle progression. In support of this is the frequent appearance of mitotic

errors in TRRAP-deficient livers, a finding that is consistent with the role of TRRAP in mitotic progression.10, 13 Together with previous findings on TRRAP-deficient cells,13 our results show that TRRAP plays a key role during entry into and progression through the cell cycle (including mitosis) owing to its association with different transcription OSBPL9 factors and expression of distinct sets of cell cycle-specific genes (Supporting Fig. 2A). However, the mechanism by which TRRAP mediates hepatocyte regeneration may involve other layers of regulation (including posttranslational modifications of key cell cycle players). Of note, we found that loss of TRRAP also compromised the proliferation of nonparenchymal cells, suggesting that TRRAP is important for cell cycle progression and proliferation of not only parenchymal cells (hepatocytes) but also of nonparenchymal cells during liver regeneration.