{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRNF168 is a pivotal E3 ubiquitin ligase that is activated in response to DNA double‐strand breaks (DSBs). Acting downstream of RNF8, RNF168 is recruited to damaged chromatin and rapidly amplifies ubiquitin signals by catalyzing site‐specific ubiquitination of histone H2A and its variant H2AX at non‐canonical residues (e.g. lysines 13–15 and 27) as well as at bidentate N‐terminal sites. These unique ubiquitin marks create a platform for the assembly of downstream repair factors—including 53BP1, BRCA1, PALB2, and others—and thereby orchestrate the recruitment and retention of key DNA damage response (DDR) mediators at DSB sites. In addition, RNF168 functions in diverse repair contexts, including heterochromatic DSB repair, telomere deprotection, and class switch recombination, and can even be the target of viral E3 ubiquitin ligases (such as HSV‐1 ICP0) that trigger its degradation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRNF168’s activity and substrate specificity are finely tuned by multiple regulatory mechanisms. Its enzymatic function depends on dedicated ubiquitin‐binding modules (including MIU and the related UMI motifs) that interact with pre‐existing ubiquitin modifications on chromatin, and its proper positioning is influenced by structural recognition of key nucleosome features (such as the acidic patch). In addition, RNF168 is dynamically regulated through post‐translational modifications: phosphorylation (for example, by mTOR–S6K, which inhibits its ligase activity), SUMOylation that may trigger liquid–liquid phase separation, and neddylation that can modulate its catalytic efficiency. The protein’s stability and chromatin residency are further controlled by deubiquitinating enzymes (like USP7, USP44, USP29, and USP14) and by interactions with other factors (for instance, PARP1 and chromatin remodelers such as SMARCA5), as well as through orchestrated interplay with auxiliary proteins (e.g. L3MBTL2). These regulatory circuits ensure that RNF168-mediated ubiquitination is precisely executed and terminated, preventing aberrant DDR signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its central role in the canonical DDR, RNF168 influences broader aspects of genome maintenance and cellular homeostasis. Its ubiquitin signaling not only directs repair pathway choice—modulating the balance between homologous recombination and non‐homologous end joining—but also regulates telomere stability and participates in responses to replication stress. Furthermore, aberrant RNF168 expression or activity is implicated in cancer biology: for example, its overabundance can enhance genomic instability and affect sensitivity to chemotherapeutic agents, while in certain contexts, RNF168 contributes to transcriptional regulation (such as promoting estrogen receptor α expression in breast cancer cells). Moreover, RNF168-mediated ubiquitination of other targets (including PARP1) adds another layer to its multifaceted role in coupling ubiquitin signaling to diverse nuclear processes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "37", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Carsten Doil, Niels Mailand, Simon Bekker-Jensen, et al. 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