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Review
. 2011 Jul 29;286(30):26267-76.
doi: 10.1074/jbc.R111.252569. Epub 2011 Jun 7.

KAP1 protein: an enigmatic master regulator of the genome

Sushma Iyengar  1 , Peggy J Farnham
Affiliations
Review

KAP1 protein: an enigmatic master regulator of the genome

Sushma Iyengar et al. J Biol Chem. .

Abstract

In mammalian cells, multiple cellular processes, including gene silencing, cell growth and differentiation, pluripotency, neoplastic transformation, apoptosis, DNA repair, and maintenance of genomic integrity, converge on the evolutionarily conserved protein KAP1, which is thought to regulate the dynamic organization of chromatin structure via its ability to influence epigenetic patterns and chromatin compaction. In this minireview, we discuss how KAP1 might execute such pleiotropic effects, focusing on genomic targeting mechanisms, protein-protein interactions, specific post-translational modifications of both KAP1 and associated histones, and transcriptome analyses of cells deficient in KAP1.

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Figures

FIGURE 1.
FIGURE 1.
Schematics of the human KAP1 protein (also called TIF1β and TRIM28) and other related proteins, including TIF1α/TRIM24, TIF1γ/TRIM33, and TIF1δ/TRIM66. The overall sequence identity between KAP1 and the other proteins is shown next to the C termini of the other proteins; the percentage sequence identity of the other proteins to the KAP1 protein in the RBCC domain and in the C-terminal PB domain is also shown. The TSS domain, the HP1 box, a domain that has been shown to bind nuclear receptors (NR Box), and a nuclear localization sequence (NLS) domain are also indicated. h, human; m, mouse.
FIGURE 2.
FIGURE 2.
Recruitment of KAP1 to the genome. A, shown is the KAP1 ChIP-seq binding pattern and position of the C2H2 ZNF genes for chromosome (Chr) 19 in HEK293 cells. A similar pattern has been observed in numerous cell types. B, shown is KAP1 binding at the 5′- and 3′-ends of two ZNF genes. (The genes are transcribed in the opposite direction, as indicated by the arrowheads.) Under the ZNF790 gene is a model illustrating recruitment of KAP1 and associated proteins to 3′-coding exons of ZNF genes. This recruitment is dependent upon interaction of the RBCC domain of KAP1 with a KRAB-ZNF that is bound to its recognition motif (indicated as TFBS); 3 molecules of KAP1 interact with a KRAB-ZNF. The PHD domain sumoylates the bromodomain, leading to recruitment of SETDB1 and Mi2α and creation of the H3K9me3 mark on nearby nucleosomes. HP1 can bind to KAP1 at the PxVxL motif and also to H3K9me3, stabilizing the bound KAP1-containing complex. Under the ZFN345 gene is a model illustrating recruitment of KAP1 to promoters. This recruitment is dependent upon interaction of KAP1 with a non-KRAB-ZNF DNA-binding protein (indicated by ? TF) that has a KAP1-interacting domain (KID) and a DBD. KAP1 interacts with this non-KRAB-ZNF DNA-binding protein via a region of KAP1 near the HP1-binding domain (HP1BD). KAP1 bound to cellular promoters does not recruit SETDB1 or result in H3K9me3. See text for details.
FIGURE 3.
FIGURE 3.
Transcriptional regulation by KAP1. A, KAP1 can repress transcription when recruited to promoters by a Gal4 DBD-KRAB fusion protein. Before binding of KAP1, the promoter is bound by RNA polymerase II (RNA Pol II) and by active chromatin marks such as H3K4me3 and H3K9Ac. Upon binding of a fusion protein consisting of a Gal4 DBD and a KRAB domain, KAP1 and associated proteins are recruited to the promoter. This recruitment results in the loss of RNA polymerase II, the loss of active chromatin marks, and the creation of the repressive H3K9me3 mark, leading to transcriptional repression. B, reduction of KAP1 has little effect on the expression of endogenous ZNF genes. Under normal conditions, the promoters of ZNF genes are covered by active chromatin marks (H3K9Ac and H3K4me3), and the exons are covered by the transcriptional elongation mark H3K36me3, even though the 3′-coding exons are bound by KAP1, SETDB1, and H3K9me3. Thus, KAP1 target genes are covered by both active and repressed marks, and the genes are transcribed. Both the promoters and 3′-exons of ZNF genes retain their normal epigenetic profile after removal of KAP1 by shRNA. See text for details. DBS, DNA-binding site.
FIGURE 4.
FIGURE 4.
Model for KAP1 involvement in DNA repair. Under normal conditions, sumoylated KAP1 is recruited to the genome via KRAB-ZNFs, resulting in H3K9me3 at nearby nucleosomes. Upon DNA damage (indicated by the double zigzag), there is a switch between the sumoylated and phosphorylated forms of KAP1 (mediated by ATM) and a rapid localization of phosphorylated KAP1 to DNA damage foci, where it may facilitate a local decondensation of chromatin, as indicated by the acetylation of His-3 and His-4 and the presence of H2AX, allowing access of DNA repair proteins such as 53BP1 and BRCA1. A return to the sumoylated form of KAP1 mediated by PP1β may assist in re-forming condensed chromatin after the DNA is repaired. See text for details. DSB, double-strand break.
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