Abstract
There are numerous forkhead transcription factors in mammalian cells but we know little about the molecular functions of the majority of these. FOXK2 is a ubiquitously expressed family member suggesting an important function across multiple cell types. Here, we show that FOXK2 binds to the SIN3A and PR-DUB complexes. The PR-DUB complex contains the important tumour suppressor protein, the deubiquitinase BAP1. FOXK2 recruits BAP1 to DNA, promotes local histone deubiquitination and causes changes in target gene activity. Our results therefore provide an important link between BAP1 and the transcription factor FOXK2 and demonstrate how BAP1 can be recruited to specific regulatory loci.
Highlights
The forkhead transcription factor family contains over 40 members and all of these contain a forkhead winged helixturn-helix DNA binding domain (1,2)
To further our understanding of FOXK2 function, we used Rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) (17) to identify novel FOXK2 binding partners. This technique is designed to maximize the chances of isolating factors that are associated with chromatin-bound FOXK2, by using formaldehyde-mediated cross-linking prior to immunoprecipitating FOXK2 (Figure 1A)
Immunopreciptations (IPs) were performed using anti-Flag antibody using extracts from cross-linked U2OS–FOXK2–HF cells which harbour Flag-tagged FOXK2 expressed at endogenous levels (12), and the resulting immunoprecipitates were analysed by mass spectrometry
Summary
The forkhead transcription factor family contains over 40 members and all of these contain a forkhead winged helixturn-helix DNA binding domain (1,2). This domain is responsible for sequence-specific DNA binding, generally to sites resembling the RYMAAYA (R = A or G; Y = C or T; M = A or C) core motif ((3,4); reviewed in (1)). Many of these proteins are expressed in a restricted or cell typespecific manner but a group of these are ubiquitously expressed across many cell types, including the related proteins FOXK1 and FOXK2. In addition to potential transcriptional roles, an alternative function in DNA repair is suggested by the observation that FOXK2 can bind to DNA containing G/Tmismatches (14)
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