Despite a lack of DNA binding activity, E1A is found on a large number of cellular promoters (5, 6)

Despite a lack of DNA binding activity, E1A is found on a large number of cellular promoters (5, 6). upregulated, p53 occupancy on target promoters is enhanced, and histone H3 lysine 9 is hyperacetylated. This is likely due to the loss of the FUBP1-mediated suppression of p53 DNA binding. We also observed that E1A stabilizes the FUBP1-p53 complex, preventing p53 promoter binding. Together, our results identify, for the first time, FUBP1 as a novel E1A binding protein that participates in aspects of viral replication and is involved in the E1A-mediated suppression of p53 function. IMPORTANCE Viral infection triggers innate cellular defense mechanisms that have evolved to block virus replication. To overcome this, viruses have counterevolved mechanisms that ensure that cellular defenses are either disarmed or not activated to guarantee successful replication. One of the key regulators of cellular stress is the tumor suppressor p53 that responds to a variety of cellular stress stimuli and safeguards the integrity of the genome. During infection, many viruses target the p53 pathway in order to deactivate it. Here we report that human adenovirus 5 coopts the cellular protein FUBP1 to prevent the activation of the p53 stress response pathway that would block viral replication. This finding adds to our understanding of p53 deactivation by adenovirus and highlights its importance in infection and innate immunity. is the first gene transcribed after infection, and its primary function is to induce the cells to enter S phase, deregulate cellular gene expression to favor viral replication, and activate the expression of viral transcription units (2). The E1A protein itself possesses no intrinsic DNA binding activity; instead, it modulates the function of cellular proteins via a large variety of interactions that alter protein function (2). Despite a lack of DNA binding activity, E1A is found on a large number of cellular promoters (5, 6). The recruitment of E1A to these cellular promoters occurs via interactions with promoter-bound factors, such as E2F-DP complexes that regulate S-phase-specific genes (7) or C-terminal binding protein 1 (CtBP1) that plays a role in E1A-mediated transformation (8). E1A is also recruited to all viral promoters via DNA-bound cellular DAPK Substrate Peptide transcriptional regulators, and it is critical for the efficient activation of many of them (9, 10). Although the induction of S phase is essential for viral replication, it also triggers cellular defense mechanisms that lead to cell cycle arrest or apoptosis (11), a highly undesirable outcome for the virus. DNA tumor viruses, such as HAdV, have therefore developed Rabbit polyclonal to SP3 multiple strategies to prevent either cell cycle arrest or apoptosis caused by the activation of the DNA damage response pathway. For HAdV, one of the primary mechanisms that prevent this undesirable outcome targets the p53 tumor suppressor protein. The viral E1B-55k protein together with E4-orf6 forms a complex with p53 that recruits the Cullin-containing ubiquitin ligase assembly that drives p53 ubiquitination and subsequent degradation via the proteasome (12). The DAPK Substrate Peptide viral E4-orf3 protein is able to suppress the activation of p53-regulated target genes via the induction of heterochromatin at p53-regulated promoter sites, preventing the expression of p53-induced genes (13). E1A also influences p53 target gene expression by associating with the Nek9 kinase located on p53-regulated promoters and driving their transcriptional silencing via an unknown mechanism (14). In addition to a direct effect on the expression of p53-regulated DAPK Substrate Peptide genes via interactions with Nek9, E1A is able to modulate p53 function indirectly by altering the activity of cofactors required for p53 transactivation, such as p300/CBP and related enzymes, which are involved in p53-mediated transactivation. p300 also directly acetylates p53 (15,C17), which is essential for p53-mediated transactivation (16). Although a DAPK Substrate Peptide number of previous studies have shown that the status of p53 in a cell can.