The transcription factor E2F1 plays a pivotal role in the control of cell proliferation and apoptosis. Recently we uncovered a novel pocket proteins-independent pathway involving PI3K/Akt and a BRCT domain-containing protein TopBP1 in the control of E2F1 Our preliminary data further demonstrate E2F can be regulated by another BRCT domain-containing protein, MCPH1/BRIT1. The pRb family members have long been considered to be the major regulators for E2F. TopBP1 and MCPH1 appear to be a new class of E2F regulators. They both contain multiple BRCT motifs and interact with the N- terminus of E2F1 through their BRCT motifs. TopBP1 is a negative regulator, whereas, MCPH1 is a positive regulator of E2F1 target genes in checkpoint/repair and apoptosis. Both proteins are also directly involved in DNA damage checkpoint activation. In this proposal, we aim to characterize the functions and mechanisms of these novel regulations governing E2F1 protein activity and stability. First, We will elucidate the mechanism by which growth factor signalings control E2F1 through TopBP1. Second, We will determine how MCPH1 regulates E2F1. How TopBP1 and MCPH1 respond to environmental milieu and regulate E2F1 activity will also be investigated. Lastly, we will investigate how E2F1 protein is induced in response to ATM phosphorylation. Upon completion of this project, we will elucidate how the proliferative and pro-apoptotic activities of E2F1 are differentially regulated. Understanding the control of E2F1 activity and stability in growth and DNA damage may provide novel approaches in harness E2F1 pro-apoptotic activity to enhance chemosensitivity.