CDW19S coordinates phasic end processing via distinct enzymatic activities

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ID: 319834
2026
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Abstract
Abstract In response to DNA double-strand breaks (DSBs), 5′-3′ resection is required for production of single-stranded DNA (ssDNA) and commitent of homologous recombination (HR). Here, we demonstrated that CDW19S, a DSB-bound 19S proteasome variant, coordinates phasic control of long-range resection in a spatial-separated manner. Phase I exploits a panel of ubiquitin modifications on RAP80 (6Kub) as a hesitation mechanism to restrain BRCA1 loading. The deubiquitinase POH1, an integral component of CDW19S, removes 6Kub to allow BRCA1 assembly with BRCA1–A complex and firing of extensive resection. Following the action of phase I apparatus that is metazoan-specific, evolutionarily conserved phase II takes the relay in more distal compartments by imposing CDW19S-engaged CRL4WDR70 E3 ligase to degrade ADRM1, leading to the full-range ssDNA production dedicated for HR activation. The phasic regulation stimulates the repositioning of 53BP1-dependent resection barriers: 6Kub removal and BRCA1 loading overcome the 53BP1/PTIP barrier in phase I, and the demolition of ADRM1 antagonizes 53BP1/RIF1. Importantly, the phasic control of extensive resection serves for the tight control of ssDNA production, securing HR activation and preventing toxic repair mechanisms. Aggregately, our work reveals a coordinative function of CDW19S facilitating sufficient end resection that is crucial for error-free DNA repair.
Reference Key
openalex_W7167509978 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Ming Zeng, Zizhi Tang, Chunyi Li, Laifeng Ren, Xiaojun Wang, Antony Carr, Cong Liu
Journal Nucleic Acids Research
Year 2026
DOI
10.1093/nar/gkag681
URL
https://doi.org/10.1093/nar/gkag681
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