Profiling the Human Protein-DNA Interactome Reveals ERK2 as a Transcriptional Repressor of Interferon Signaling

Abstract

SUMMARY Protein-DNA interactions (PDIs) mediate a broad range of functions essential for cellular differentiation, function, and survival. However, it is still a daunting task to comprehensively identify and profile sequence-specific PDIs in complex genomes. Here, we have used a combined bioinformatics and protein microarray-based strategy to systematically characterize the human protein-DNA interactome. We identified 17,718 PDIs between 460 DNA motifs predicted to regulate transcription and 4,191 human proteins of various functional classes. Among them, we recovered many known PDIs for transcription factors (TFs). We also identified a large number of new PDIs for known TFs, as well as for previously uncharacterized TFs. Remarkably, we found that over three hundred proteins not previously annotated as TFs also showed sequence-specific PDIs, including RNA binding proteins, mitochondrial proteins, and protein kinases. One of such unconventional DNA-binding proteins, MAPK1, acts as a transcriptional repressor for interferon gamma-induced genes.

Phosphorylation of Eukaryotic Translation Initiation Factor 4B (EIF4B) by Open Reading Frame 45/p90 Ribosomal S6 Kinase (ORF45/RSK) Signaling Axis Facilitates Protein Translation during Kaposi Sarcoma-associated Herpesvirus (KSHV) Lytic Replication

“…The case for their role in transcriptional regulation is also strengthened by recent discoveries that the ERK and RSK kinases are associated with chromosomes (65)(66)(67). We have shown that RSK1 and RSK2 are colocalized with ORF45 in both the cytoplasm and nucleus (17).…”

Environmental Regulation of Prions in Yeast

“…Protein microarrays have been applied to detect proteinprotein, protein-lipid, protein-DNA and protein-viral RNA interactions [17,21,36,37]. Here, we describe the use of protein microarrays for the detection of protein-RNA interactions.…”

Regulation of chromatin by histone modifications

“…For the majority of kinases, however, it is unclear how the enzyme is accurately recruited to its site of action on chromatin. In a few cases, exemplified by the mammalian MAPK1 enzyme, the kinase possesses an intrinsic DNA-binding domain with which it is tethered to the DNA [13]. This may be sufficient for specific recruitment, similar to bona fide DNA-binding transcription factors.…”