The E2F transcription factor family plays a crucial role in cell cycle progression and proliferation. This study aimed to identify additional E2F target genes by developing a protocol that combines immunoprecipitation of cross-linked protein-DNA complexes with DNA microarray analysis. The protocol was applied to identify genomic binding sites for E2F4 and E2F1 in living human cells. The results revealed that E2F4 binds to the promoters of 127 genes, with a subset also bound by E2F1. These targets included genes involved in DNA replication, cell cycle control, DNA repair, and multiple checkpoints. The study confirmed the functional relevance of E2F binding to several novel targets using conventional ChIP analysis and gene expression profiling. Notably, E2F4 binds to genes involved in DNA repair and checkpoints, suggesting that E2F integrates cell cycle progression with DNA repair and checkpoint regulation. The findings highlight the broader role of E2F in coordinating the expression of genes essential for both DNA synthesis and surveillance.The E2F transcription factor family plays a crucial role in cell cycle progression and proliferation. This study aimed to identify additional E2F target genes by developing a protocol that combines immunoprecipitation of cross-linked protein-DNA complexes with DNA microarray analysis. The protocol was applied to identify genomic binding sites for E2F4 and E2F1 in living human cells. The results revealed that E2F4 binds to the promoters of 127 genes, with a subset also bound by E2F1. These targets included genes involved in DNA replication, cell cycle control, DNA repair, and multiple checkpoints. The study confirmed the functional relevance of E2F binding to several novel targets using conventional ChIP analysis and gene expression profiling. Notably, E2F4 binds to genes involved in DNA repair and checkpoints, suggesting that E2F integrates cell cycle progression with DNA repair and checkpoint regulation. The findings highlight the broader role of E2F in coordinating the expression of genes essential for both DNA synthesis and surveillance.