Evolutionarily recent TFs partake in human cell cycle regulation [BRDU]

The cell cycle is a fundamental process in eukaryotic reproduction, controlled by a highly conserved core signaling cascade. However, the role of recently evolved proteins in cell cycle regulation remains unclear, largely because conservation is often assumed to be essential for function. In this study, we systematically map the influence of evolutionarily recent transcription factors (TFs) on human cell cycle progression. We find that the genomic targets of select recent TFs, many of which belong to the rapidly evolving Krüppel-associated box (KRAB) zinc-finger proteins (KZFP) family, exhibit synchronized cell cycle expression. Systematic perturbation studies reveal that silencing recent TFs disrupts normal cell cycle progression, which we experimentally confirm for ZNF519, a simian-restricted KZFP. Further, we show that the therian-specific KZFP ZNF274 sets the cell cycle expression and replication timing of hundreds of clustered genes. These findings highlight an underappreciated level of lineage specificity in cell cycle regulation and underline the power of forward genetics in comprehensively mapping cell function. Overall design: Romain, Forey