Abstract
DRIL1 is an ARID family transcription factor that can immortalize primary mouse fibroblasts, bypass RASV12-induced cellular senescence and collaborate with RASV12 or MYC in mediating oncogenic transformation. It also activates immunoglobulin heavy chain transcription and engages in heterodimer formation with E2F to stimulate E2F-dependent transcription. Little, however, is known about the regulation of DRIL1 activity. Recently, DRIL1 was found to interact with the SUMO-conjugating enzyme Ubc9, but the functional relevance of this association has not been assessed. Here, we show that DRIL1 is sumoylated both in vitro and in vivo at lysine 398. Moreover, we provide evidence that PIASy functions as a specific SUMO E3-ligase for DRIL1 and promotes its sumoylation both in vitro and in vivo. Furthermore, consistent with the subnuclear localization of PIASy in the Matrix-Associated Region (MAR), SUMO-modified DRIL1 species are found exclusively in the MAR fraction. This post-translational modification interferes neither with the subcellular localization nor the DNA-binding activity of the protein. In contrast, DRIL1 sumoylation impairs its interaction with E2F1 in vitro and modifies its transcriptional activity in vivo, driving transcription of subset of genes regulating leukocyte fate. Taken together, these results identify sumoylation as a novel post-translational modification of DRIL1 that represents an important mechanism for targeting and modulating DRIL1 transcriptional activity.
Highlights
E2FBP1/ARID3A/DRIL1 was originally isolated as a novel E2F1 heterodimeric partner that stimulates E2F-dependent transcription [1]
We recently demonstrated that DRIL1 allows primary mouse fibroblasts (MEFs) to efficiently bypass both spontaneous and activated RAS-induced senescence by deregulating the Rb/ E2F1 pathway [10]
DRIL1 was previously described to interact with Ubc9, the only known Small Ubiquitin-related MOdifier (SUMO) E2 conjugating enzyme [14]
Summary
E2FBP1/ARID3A/DRIL1 (hereafter referred to as DRIL1) was originally isolated as a novel E2F1 heterodimeric partner that stimulates E2F-dependent transcription [1]. The mouse ortholog of DRIL1, B cell regulator of Ig heavy chain transcription (BRIGHT), exhibits specific matrix-attachment regions (MARs) binding properties and regulates immunoglobulin transcription at late stages of B lymphocyte differentiation [6]. The functional connection of DRIL1 to both Rb/E2F1 and p53 tumor suppressor pathways, as well as its pivotal function in promoting either cellular proliferation or growth arrest, implies a tight and finely tuned regulation of DRIL1 activity and binding affinities. Such regulatory mechanisms of DRIL1 function remain largely unknown
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