ArticleNature communications2026
53BP1-independent Shieldin-BRCA1 antagonism at replication-coupled double-strand breaks.
Article in Nature communications, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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8 authors.
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Abstract
BRCA1-deficient tumors are hypersensitive to PARP inhibitors (PARPi) due to impaired homologous recombination (HR). The 53BP1-Shieldin complex inhibits end resection at replication-independent DNA double-strand breaks (DSBs), promoting PARPi sensitivity in BRCA1-deficient cells. However, its role in replication-coupled DSBs is less clear. Here, we show that loss of Shld2 or Shld3, but not 53bp1, confers PARPi resistance in mouse embryonic stem cells lacking a functional BRCA1 BRCT domain. Unlike 53bp1 loss, deletion of Shld2 or Shld3 partially restores HR at replication-coupled DSBs, reduces BRCA1-linked insertion/deletion signatures, and promotes RAD51 loading. This 53BP1-independent function requires the CST complex and counteracts residual BRCA1 coiled-coil domain activity in RAD51 loading. Shld2 loss also confers PARPi resistance in Bard1-null cells retaining residual BRCA1, but not in cells expressing RING-less BRCA1 with degraded BARD1. These findings identify a 53BP1-independent function for Shieldin in sustaining HR deficiency in BRCA1-deficient cells, providing new mechanistic insights into PARPi resistance.
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