Identification of novel interaction between Promyelocytic Leukemia protein and human Alteration/Deficiency in Activation 3 coactivator and its role in DNA damage response

Abstract

Human Alteration/Deficiency in Activation 3 (hADA3) is an interesting transcriptional coactivator adaptor protein with predominant nuclear localization. Even though it has been shown to be an important mediator of diverse cellular processes including embryonic development, cell cycle progression and maintenance of genomic stability, the molecular mechanisms underlying its role in apoptosis and DNA damage response remain elusive. Our study for the first time revealed that hADA3 exhibits punctate nuclear pattern which interestingly colocalizes with Promyelocytic Leukemia Nuclear Bodies (PML-NBs). We also provide novel evidence for the physical interaction between them, which is further enhanced following DNA damage. Moreover, we demonstrate that cells expressing a hADA3 mutant which is unable to interact with PML, displayed impaired apoptosis indicating a clear role of hADA3 in PML-mediated apoptosis. These findings, therefore, highlight a previously unappreciated function of hADA3 and establish its novel functional link with PML in provoking DNA damage response.