Abstract
KAP1 (KRAB-associated protein 1) is best known as a co-repressor responsible for inducing heterochromatin formation, notably at transposable elements. However, it has also been observed to bind the transcription start site of actively expressed genes. To address this paradox, we characterized the protein interactome of KAP1 in the human K562 erythro-leukaemia cell line. We found that the regulator can associate with a wide range of nucleic acid binding proteins, nucleosome remodellers, chromatin modifiers and other transcription modulators. We further determined that KAP1 is recruited at actively transcribed polymerase II promoters, where its depletion resulted in pleomorphic effects, whether expression of these genes was normally constitutive or inducible, consistent with the breadth of possible KAP1 interactors.This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation’.
Highlights
KAP1/TRIM28 is a master regulator critical to processes such as stem cell self-renewal and DNA-damage response [1,2,3,4,5,6]
Its best-described function far is the binding through sequence-specific targeting Krüppel-associated box domain-containing-zinc finger proteins (KZFPs) to transposable elements (TEs), which leads to the transcriptional silencing of these genetic units [7,8,9,10,11,12]
Known partners of KAP1, such as components of the nucleosome remodelling and deacetylase (NuRD) complex and HP1 proteins, associated with overexpressed KAP1 in K562 cells. These findings were in agreement with previous MS/MS studies performed by our group with the endogenous protein in human embryonic stem cells, where we found significant enrichment of the same cofactors [23]
Summary
KAP1/TRIM28 is a master regulator critical to processes such as stem cell self-renewal and DNA-damage response [1,2,3,4,5,6]. Its best-described function far is the binding through sequence-specific targeting Krüppel-associated box domain-containing-zinc finger proteins (KZFPs) to transposable elements (TEs), which leads to the transcriptional silencing of these genetic units [7,8,9,10,11,12] At these sites, KAP1 acts as a scaffold protein for the formation of a heterochromatin-inducing machinery comprising HP1 (heterochromatin protein 1), the histone methyl-transferase SETDB1, the nucleosome remodelling and deacetylase (NuRD) complex and the histone demethylase KDM1A [9,13,14,15,16,17]. Another study centred on KAP1 recruitment at gene promoters found it to correlate with paused PolII genome-wide, and while the molecular mechanisms of its recruitment remained unexplored, there was evidence of KAP1-mediated transcriptional control for inducible genes [21]. We present proteomic and functional data indicating that KAP1 can associate with a wide range of nucleic acid binding proteins, nucleosome remodellers and other transcriptional modulators, that it can associate with promoters recognized by PolII, and that its impact at these genetic loci is diverse, as predicted from the breadth of its protein interactome
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