Abstract
Maintenance of genome stability is a crucial priority for any organism. To meet this priority, robust signalling networks exist to facilitate error-free DNA replication and repair. These signalling cascades are subject to various regulatory post-translational modifications that range from simple additions of chemical moieties to the conjugation of ubiquitin-like proteins (UBLs). Interferon Stimulated Gene 15 (ISG15) is one such UBL. While classically thought of as a component of antiviral immunity, ISG15 has recently emerged as a regulator of genome stability, with key roles in the DNA damage response (DDR) to modulate p53 signalling and error-free DNA replication. Additional proteomic analyses and cancer-focused studies hint at wider-reaching, uncharacterised functions for ISG15 in genome stability. We review these recent discoveries and highlight future perspectives to increase our understanding of this multifaceted UBL in health and disease.
Highlights
Ubiquitylation is one of the most studied post-translational modifications (PTMs) and involves the conjugation of ubiquitin (8.5 kDa), a highly conserved 76 amino-acid protein, primarily onto lysines of target proteins via a three-step ATP-dependent enzymatic cascade formed by an E1-activating enzyme, an E2-conjugating enzyme and an E3 ligase [1]
Termed ubiquitin cross-reactive protein (UCRP) after its ability to cross-react with ubiquitin antibodies [14], it was later renamed to Interferon Stimulated Gene 15 (ISG15) [18,19]
The two ISG15 ubiquitin-like proteins (UBLs) domains differ in molecular function, with the solvent-exposed N-terminal domain facilitating ISG15 transfer from E2 to substrate and the C-terminal domain being crucial for E1-mediated ISG15 activation and transthiolation [20,22]
Summary
ISG15 was the first UBL to be discovered in 1979, four years after ubiquitin [16,17]. An aspect of ISG15 distinct from ubiquitin is that, similar to FAT10, it is comprised of two UBL domains [1]. While the N- and C-terminal UBL domains of ISG15 possess only ~30% sequence homology with ubiquitin, they share strikingly similar tertiary structures and display comparable as well as distinct areas of electrostatic surface potentials with ubiquitin (Figure 1C) [8,20,21,22,23]. BiomoleUcuFlMes 120[1192, ]9,, xUBQLN4 [69], SUMO1, SUMO2 and SUMO3 [70]; sequence similarity to ubiquitin is of 32 highlighted in the outermost ring ranging from GABARAP (9.59%) in red over a white midpoint to NNEEDDDD88 ((5588%%)) iinn bblluuee. X(sPe_a00tu1r3t7le2;71X7P.2_)0, 27C6h8e9lo3n1i4a.1m), yNdaostec(hsiesascututartules; (tXigPe_r02s7n6a8k9e3;1X4.P1_),02N65o4te3c8h0is4),scDuatantiuosre(rtiioge(zrebsrnaafikseh;; XNPP__002061514931800948).,1)DaanndioCryenroioglo(zsseubsrasefmishila; eNvisP(_t0o0n1g1u9e10s9o8le.1; )NaPn_d001C2y8n7o9g3l5o)s.suAslisgenmmileanevtsisw(etorengeuneersaotleed; NusPi_n0g0T1-2C87o9ff3e5e).[7A9l]iganmd evnistusawliesreedgwenitehraEtSePdriupstin3g[8T0-]C. offee [79] and visualised with ESPript 3 [80]
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