KAPtain in charge of multiple missions: Emerging roles of KAP1

Abstract

KAP1/TRIM28/TIF1β was identified nearly twenty years ago as a universal transcriptional co-repressor because it interacts with a large KRAB-containing zinc finger protein (KRAB-ZFP) transcription factor family. Many studies demonstrate that KAP1 affects gene expression by regulating the transcription of KRAB-ZFP-specific loci, trans-repressing as a transcriptional co-repressor or epigenetically modulating chromatin structure. Emerging evidence suggests that KAP1 also functions independent of gene regulation by serving as a SUMO/ubiquitin E3 ligase or signaling scaffold protein to mediate signal transduction. KAP1 is subjected to multiple post-translational modifications (PTMs), including serine/tyrosine phosphorylation, SUMOylation, and acetylation, which coordinately regulate KAP1 function and its protein abundance. KAP1 is involved in multiple aspects of cellular activities, including DNA damage response, virus replication, cytokine production and stem cell pluripotency. Moreover, knockout of KAP1 results in embryonic lethality, indicating that KAP1 is crucial for embryonic development and possibly impacts a wide-range of (patho)physiological manifestations. Indeed, studies from conditional knockout mouse models reveal that KAP1-deficiency significantly impairs vital physiological processes, such as immune maturation, stress vulnerability, hepatic metabolism, gamete development and erythropoiesis. In this review, we summarize and evaluate current literatures involving the biochemical and physiological functions of KAP1. In addition, increasing studies on the clinical relevance of KAP1 in cancer will also be discussed.

Keywords: KRAB domain-associated protein 1, Transcriptional co-repressor, Post-translational modification, Chromatin remodeling, KRAB-containing zinc finger protein

Core tip: This review article primarily summarizes the current findings of KAP1/TRIM28/TIF1β, with focuses on its biochemical and physiological functions. Both the canonical transcriptional co-repressor function and the transcriptional-independent roles of KAP1 are discussed in detail. We highlight the post-translational modifications and the compartmentalized localization of KAP1 and suggest that the function of KAP1 could be spatial and temporal regulated in multiple physiological circumstances. Finally, we summarize the clinical relevance of KAP1 in cancer and discuss the possibility to translate the mechanistic studies of KAP1 to human pathophysiology in the future.