AI Insight
Researchers have discovered how the BRCA1-A complex, an enzyme involved in DNA repair and genome stability, selectively removes long chains of a specific ubiquitin modification (K63-linked) from proteins. Using a novel probe and cryo-electron microscopy structures, they revealed that BRCA1-A employs multiple ubiquitin-binding sites to grip and progressively shorten these chains, a mechanism that only works efficiently on extended chains. This explains why BRCA1-A specifically targets long K63-linked polyubiquitin chains rather than shorter ones or chains with different linkage types.
Why it matters
Understanding how BRCA1-A recognizes and processes specific ubiquitin chains is critical for comprehending DNA damage response mechanisms, which are frequently disrupted in cancer. This knowledge could inform therapeutic strategies targeting ubiquitin signaling pathways in diseases where BRCA1 function is compromised, particularly breast and ovarian cancers.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
The BRCA1-A complex is a multi-subunit, metallo-deubiquitinating enzyme (metallo-DUB) involved in genome maintenance. BRCA1-A displays strict specificity for K63-linked ubiquitin, with a strong preference for long chains, but the mechanistic basis for this selectivity has remained unclear. To address this, we developed a novel activity-based probe that is specific for metallo-DUBs and mimics di- or polyubiquitin chains of any linkage (di- and poly-ubiquitinATA). We solved cryoEM structures of BRCA1-A bound to K63-linked probe chains of various length, capturing multiple conformational and catalytic states. The structures reveal how allosteric regulation of catalysis occurs within the complex and how BRCA1-A uses auxiliary ubiquitin-binding sites to engage substrate by avidity and to trigger processive cleavage. Crucially, avidity and processivity can only apply to long polyubiquitin chains, explaining BRCA1-A’s substrate preference. Together, these results establish BRCA1-A as a chain-shortening DUB specialised for trimming extended K63-linked polyubiquitin chains.