Activating transcription factor 7-interacting protein 1 (ATF7IP) is a multifunctional protein involved in various cellular processes. It has been shown to interact with methylated DNA-binding domain protein 1 (MBD1) and MBD1-containing chromatin-associated factor 1 (MCAF1), also known as ATFaassociated modulator (AM) [1]. ATF7IP is implicated in the maintenance of X chromosome inactivation (XCI) through its repressive context, where it mediates MBD1-dependent transcriptional silencing by recruiting and catalytically activating the histone H3K9 methyltransferase SETDB1 [2]. Furthermore, ATF7IP contains at least two functional binding surfaces for other proteins, such as SETDB1 and MBD1, and plays a role in efficient transcriptional silencing mediated by the SETDB1 complex [3][4]. It has also been identified as a transcriptional cofactor involved in histone gene expression and cellular senescence [5]. ATF7IP is recognized as a SETDB1-interacting protein and is essential for heterochromatin formation by the HUSH complex [6]. Additionally, ATF7IP has been reported to inhibit Il2 expression, regulating Th17 responses, and is an essential cofactor in SETDB1 enzymatic activity and nuclear localization [7]. Moreover, ATF7IP is involved in the regulation of SETDB1 nuclear localization and its enzymatic activity, as well as in increasing the levels of its ubiquitinated and more enzymatically active forms [8][9]. The protein also undergoes tri-methylation by G9a/GLP, recruiting the chromodomain protein MPP8, suggesting its involvement in gene regulation [10]. Interestingly, ATF7IP's methylation partially contributes to the function of the HUSH complex, as preventing K16 methylation led to a delay in HUSH complex silencing of a virally introduced transgene [11].
References:
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[8] T. Tsusaka, C. Shimura, & Y. Shinkai, "Atf7ip regulates setdb1 nuclear localization and increases its ubiquitination", Embo Reports, vol. 20, no. 12, 2019. https://doi.org/10.15252/embr.201948297
[9] Y. Shinkai, T. Tsusaka, K. Fukuda, C. Shimura, & M. Kato, "The fibronectin type-iii (fniii) domain of atf7ip contributes to efficient transcriptional silencing mediated by the setdb1 complex ",, 2020. https://doi.org/10.21203/rs.3.rs-44959/v2
[10] T. Tsusaka, M. Kikuchi, T. Shimazu, T. Suzuki, Y. Sohtome, M. Akakabeet al., "Tri-methylation of atf7ip by g9a/glp recruits the chromodomain protein mpp8", Epigenetics & Chromatin, vol. 11, no. 1, 2018. https://doi.org/10.1186/s13072-018-0231-z
[11] E. Cornett, L. Ferry, P. Defossez, & S. Rothbart, "Lysine methylation regulators moonlighting outside the epigenome", Molecular Cell, vol. 75, no. 6, p. 1092-1101, 2019. https://doi.org/10.1016/j.molcel.2019.08.026