UBA80 and UBA52 fine-tune RNF168-dependent histone ubiquitination and DNA repair

• Published in: The Journal of biological chemistry Vol. 299; no. 8; p. 105043
• Main Authors: Lee, Seong-Ok, Kelliher, Jessica L., Song, Wan, Tengler, Kyle, Sarkar, Aradhan, Dray, Eloise, Leung, Justin W.C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-08-2023; American Society for Biochemistry and Molecular Biology
• Subjects: 53BP1; acidic patch; DNA Damage; DNA Repair; Histones - metabolism; Humans; nucleosome; Nucleosomes - genetics; ribosomal proteins; Ribosomal Proteins - metabolism; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; ribosomal proteins; DDR; IRIF; DNA damage; 53BP1; nucleosome; GST; IR; acidic patch; SFB
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/j.jbc.2023.105043

The ubiquitin signaling pathway is crucial for the DNA damage response pathway. More specifically, RNF168 is integral in regulating DNA repair proteins at damaged chromatin. However, the detailed mechanism by which RNF168 is regulated in cells is not fully understood. Here, we identify the ubiquitin-ribosomal fusion proteins UBA80 (also known as RPS27A) and UBA52 (also known as RPL40) as interacting proteins for H2A/H2AX histones and RNF168. Both UBA80 and UBA52 are recruited to laser-induced micro-irradiation DNA damage sites and are required for DNA repair. Ectopic expression of UBA80 and UBA52 inhibits RNF168-mediated H2A/H2AX ubiquitination at K13/15 and impairs 53BP1 recruitment to DNA lesions. Mechanistically, the C-terminal ribosomal fragments of UBA80 and UBA52, S27A and L40, respectively, limit RNF168-nucleosome engagement by masking the regulatory acidic residues at E143/E144 and the nucleosome acidic patch. Together, our results reveal that UBA80 and UBA52 antagonize the ubiquitination signaling pathway and fine-tune the spatiotemporal regulation of DNA repair proteins at DNA damage sites.