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Molecular triage and isoform protection safeguard ubiquitin chain editing on DNA

Year: 2026
Type: article
Abstract: In an accompanying study, we identify the RPA-ZUP1 complex as a ubiquitin chain-editing machine that promotes removal of RPA from ssDNA. Because loss of ZUP1 causes pathological RPA trapping on ssDNA, cells must preserve a functional RPA-ZUP1 pool to sustain RPA turnover. How this homeostasis is achieved is unknown. Here, we show that ZUP1 is subject to ubiquitin-dependent fate control. ZUP1 ubiquitination promotes recruitment of p97/VCP and ATXN3, defining a molecular triage pathway that protects ZUP1 from premature proteasomal degradation. Opposing this, the E3 ligases UBR5 and HUWE1 define a degradative branch that limits ZUP1 abundance, with HUWE1 restricting its accumulation on damaged chromatin. We further show that cells express a naturally occurring ZUP1 isoform resistant to efficient ubiquitination and turnover, suggesting that isoform diversity provides a protected pool of chain-editing activity. Together, these findings define a homeostatic system that preserves ZUP1 while limiting its persistence on damaged chromatin.
Source: Cell Reports
DOI: 10.1016/j.celrep.2026.118137
Language: English
Open Access status: gold
Estimated APC paid: $5,620
Funders: Brasenose College, University of Oxford, Cancer Research UK, University of Oxford, Medical Research Council, Lady Margaret Hall, University of Oxford, John Fell Fund, University of Oxford, Oxford University Press
OpenAlex ID: W7222828822
FWCI:
Cites: 80
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Related to: 10