Function
KAP-1 has many differents functions and some of them have yet to be studied. KAP-1 is involved in the regulation of transcription, the reparation of DNA damage but also in the cellular differenciation and proliferation and in the apoptosis.
Regulation of transcription
KAP-1 acts as a transcriptional corepressor for KRAB-ZFP proteins (KRAB domain-containing zinc finger proteins), which are proteins containing a KRAB domain. Indeed, KAP-1 make the link between the KRAB domain of KRAB-ZFPs and the transcriptional repression machinery. Because KAP-1 is not able to bind directly the DNA, it has to do a protein-protein interaction. This interaction takes place in the TRIM sequence. KAP-1 can thus coordinate and recruit to the promoter regions of KRAB target genes several components of gene silencing machinery, like the histone deacetylase complex NuRD or the histone methyltransferase SETDB1 (which specifically methylates histone H3 at Lys-9 (H3K9me)). In this way, KAP-1 is able to change the form of the chromatin and to do histones modifications at target sites, particurlay by using sumoylation. Indeed, it has recently been reported that sumoylation, a post translationnal modification which affects lysines, influences the function of KAP-1 as transcriptional co-repressor.
The lysine sumoylation can change the conformation and thus the function of a protein and its interactions with others molecules. In this way, sumoylation of KAP-1 can impact the transcriptional control that it made. The sumoylation of KAP-1 recruit the SETDB1 histone methyltransferase and the NuRD remodeling complex by binding sumo proteins to interacting sequences. This binding leads to the remodeling of chromatin and modify the target gene. This phenomenon occurs within the tandem PHD-bromodomain but the recognition of the KRAB domain occurs in the RBCC sequence.
The strongest KAP-1 binding site is the 3-ends of ZNF genes (of course present in all KRAB-ZFPs proteins) but recent ChIP-seq experiments have identified thousands of KAP1-binding sites.
DNA damage repair response
KAP-1 also plays a role in the repair of DNA when it is damaged. These damages are cytotoxic DNA lesions and can be for example double-strand breaks (DSB). These damages requires the action of the nuclear protein kinase ATM. For example, when the DNA is damaged by DSB, ATM allows the relaxation of the chromatin to allow to the DNA repair proteins to do their job. The effector of this interaction is precisely KAP-1. Indeed, in response to DSB, KAP-1 is phosphorylated thanks to the ATM on the Serine 824. In this way, without KAP-1, there is no more relaxation of the chromatin and the cell become hypersensitive to DSB-inducing agents.
The hypothesis is thus that the phosphorylation of KAP-1 results in the loss of sumoylated KAP-1 form, which is the activated form of KAP-1. That can lead to the derepression of the target genes of KAP-1. In this way, we can say that it exists an equilibrium between the phosphorylated and the sumoylated forms of KAP-1, which influences its function of repression.
Disease
Relevance
Structural highlights
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