Updated project metadata. The HTRA1 gene encoding an evolutionary conserved protein quality control factor can be epigenetically silenced or inactivated by mutation under pathologic conditions such as cancer. Recent evidence suggests that loss of HTRA1 function causes multiple phenotypes including acceleration of cell growth, delayed onset of senescence, centrosome amplification and polyploidy suggesting an implication in the regulation of the cell cycle. To address this model, we performed a large-scale proteomics study to correlate the abundance of proteins and HTRA1 levels in various cell cycle phases using label-free quantification mass spectrometry. These data indicate that the levels of 4723 proteins fluctuated in a cell cycle-dependent, 2872 in a HTRA1-dependent and 1530 in a cell cycle- and HTRA1-dependent manner. The large number of proteins affected by the modulation of HTRA1 levels support its general role in protein homeostasis. Moreover, the detected changes in protein abundance in combination with pull down data implicate HTRA1 is in numerous cell cycle events such as DNA replication, chromosome segregation and cell cycle dependent apoptosis. These results highlight the wide implications of HTRA1 in cellular physiology