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<p><i>BRCA1</i>-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 <i>BRCA1</i>-deficient cells. However, its role in replication-coupled DSBs is less clear. Here, we show that loss of <i>Shld2</i> or <i>Shld3</i>, but not <i>53bp1</i>, confers PARPi resistance in mouse embryonic stem cells lacking a functional BRCA1 BRCT domain. Unlike <i>53bp1</i> loss, deletion of <i>Shld2</i> or <i>Shld3</i> partially restores HR at replication-coupled DSBs, reduces <i>BRCA1</i>-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. <i>Shld2</i> loss also confers PARPi resistance in <i>Bard1</i>-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 <i>BRCA1</i>-deficient cells, providing new mechanistic insights into PARPi resistance.</p>

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53BP1-independent Shieldin-BRCA1 antagonism at replication-coupled double-strand breaks

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月29日

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  • Yi-Li Feng,
  • Meng Wang,
  • Ge Li,
  • Ruo-Dan Chen,
  • Rui Yao,
  • Shun-Li Dong,
  • Xiu-Jun Cai,
  • An-Yong Xie

摘要

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.