KAP-1: Many Names, Even More Functions

Krüppel-associated box (KRAB) domain-associated protein 1 (KAP-1), also known as tripartite motif-containing 28 (TRIM28), transcriptional intermediary factor 1 beta (TIF1β), and KRAB-A-interacting protein 1 (KRIP1) was first identified over 20 years ago.1 Since then, the function of KAP-1 in numerous cellular processes has been described, including in neurology, stress behavior, immunology, developmental biology, cellular proliferation and maturation, virology, genome integrity, cancer biology, and DNA damage response.1,2

Central to KAP-1’s role in these processes is its ability to influence epigenetic patterns and chromatin compaction, thereby regulating the dynamic organization of chromatin structure.1 These and other roles of KAP-1 are mediated through its function as an interacting protein for KRAB zinc finger proteins (KRAB-ZFPs). The conserved KRAB repression domain is present in many transcription factors. Binding of KAP-1 to this domain results in transcriptional co-repression.3 The action of KAP-1 is not restricted to its interaction with KRAB-ZFPs, however, in that transcription factors that lack the KRAB-ZFP domain can also be regulated by KAP-1; examples of such transcription factors include c-Myc and E2F transcription factor 1 (E2F1).4,5

KAP-1 and other co-repressors may act through 1) recruitment of enzymes that modify histones by addition or removal of acetyl groups; 2) regulation of nucleosome spacing by modulation of ATP-dependent nucleosome-remodeling enzymes such as chromodomain helicase DNA binding protein 3 (CHD3) and 4 (CHD4); or 3) stabilization of chromatin by recruitment of specific proteins such as heterochromatin protein (HP1), which binds to methylated histones and maintains their closed state. In any of these mechanisms, transcriptional silencing can be achieved by compaction and/or stabilization of chromatin to form heterochromatin.3,6

Regulation of the gene repressive function of KAP-1 is coordinately achieved through post-translational modification of KAP-1, namely via sumoylation or phosphorylation.1-3,6 Indeed, the repressive capacity of KAP-1 is controlled by its existence in either a sumoylated or phosphorylated state, in that sumoylated and phosphorylated KAP-1 are involved in transcriptional repression and DNA repair, respectively.7

Under normal conditions, KRAB-ZFPs recruit sumoylated KAP-1 to the genome. Upon DNA damage, robust and transient ATM serine/threonine kinase-mediated phosphorylation of KAP-1 occurs. Subsequently, KAP-1 is rapidly localized to the area of DNA damage, where it may facilitate localized chromatin decondensation. This decondensation in turn allows access of DNA repair proteins to the area of damage. Following DNA damage repair, the chromatin may be re-condensed following KAP-1 sumoylation.1

At present, it’s clear that the function of KAP-1 is highly dependent on post-translational modifications; sumoylated KAP-1 is involved in transcriptional repression, whereas phosphorylated KAP-1 is involved in DNA repair. Future work will no doubt continue to elucidate the diverse cellular processes in which KAP-1 plays a role and the mechanisms underlying these influences.

Detection of human KAP-1 in FFPE ovarian carcinoma by IHC.

Detection of human KAP-1 in FFPE ovarian carcinoma by IHC. Antibody: Rabbit anti-KAP-1 recombinant monoclonal [BL-248-2G6] (A700-014). Secondary: HRP-conjugated goat anti-rabbit IgG (A120-501P). Substrate: DAB.

Detection of human Phospho KAP-1 (S824) by immunocytochemistry.

Detection of human Phospho KAP-1 (S824) by immunocytochemistry. Antibody: Rabbit anti-Phospho KAP-1 (S824) recombinant monoclonal antibody [BL-246-7B5] (A700-013) used at of 1:100. Secondary: DyLight® 594-conjugated goat anti-rabbit IgG (A120-201D4). Counterstain: Phalloidin conjugated Alexa Fluor® 488 (green).


References

1. Iyengar S, Farnham PJ. 2011. KAP1 protein: an enigmatic master regulator of the genome. J Biol Chem. Jul;286(30):26267-76.

2. Cheng C-T, Kuo C-Y, Ann DK. 2014. KAPtain in charge of multiple missions: emerging roles of KAP1. World J Biol Chem. Aug;5(3):308-20.

3. Friedman JR, Fredericks WJ, Jensen DE, et al. 1996. KAP-1, a novel corepressor for the highly conserved KRAB repression domain. Genes Dev. Aug;10(16):2067-78.

4. Satou A, Taira T, Iguchi-Ariga SM, Ariga H. 2001. A novel transrepression pathway of c-Myc. Recruitment of a transcriptional corepressor complex to c-Myc by MM-1, a c-Myc-binding protein. J Biol Chem. Dec;276(49):46562-7.

5. Wang C, Rauscher FJ, Cress WD, Chen J. 2007. Regulation of E2F1 function by the nuclear corepressor KAP1. J Biol Chem. Oct;282:29902-9.

6. Ryan RF, Schultz DC, Ayyanathan K, et al. 1999. KAP-1 co-repressor protein interacts and colocalizes with heterochromatic and euchromatic HP1 proteins: a potential role for Krüppel-associated box-zinc finger proteins in heterochromatin-mediated gene silencing. Mol. Cell Biol. Jun;19(6):4366-78.

7. Li X, Lin HH, Chen H, et al. 2010. SUMOylation of the transcriptional corepressor KAP1 is regulated by the serine and threonine phosphatase PP1. Sci Signal. Apr;3(119):ra32.