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<p>The regressed arms of reversed replication forks exhibit structural similarities to one-ended double-stranded breaks and need to be protected against uncontrolled nucleolytic degradation. Here, we identify MSANTD4 (Myb/SANT-like DNA-binding domain-containing protein 4), a functionally uncharacterized protein that uniquely counters the replication protein A (RPA)–Bloom (BLM)/Werner syndrome helicase (WRN)–DNA replication helicase/nuclease 2 (DNA2) complex to safeguard reversed replication forks from detrimental degradation, independently of the breast cancer susceptibility proteins (BRCA1/2)–DNA repair protein RAD51 pathway. MSANTD4 specifically interacts with the junctions between single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in DNA substrates harboring a 3′ overhang, which resemble the structural features of regressed arms processed by WRN–DNA2. This DNA-binding capability allows MSANTD4 to accumulate at reversed forks, strategically antagonizing the RPA–BLM/WRN–DNA2 complex by impeding its access to the ssDNA–dsDNA junction of the regressed arms. Loss of MSANTD4 exacerbates genome instability induced by replication stress in BRCA1/2-deficient cells. Our findings unveil a collaborative defense mechanism orchestrated by MSANTD4 and BRCA1/2–RAD51, effectively counteracting nucleolytic attacks on the regressed arms and synergistically preserving the integrity of reversed forks.</p><p></p>

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Synergistic protection of nascent DNA at stalled forks by MSANTD4 and BRCA1/2–RAD51

  • 期刊论文

  • 发表日期：

    2025年1月14日

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  • Haihua Xie,
  • Lizhi Song,
  • Genxiang Mao,
  • Jinhua Han,
  • Jiali Pu,
  • Zhibing Wu,
  • Jun Chen,
  • Jianwei Zhou,
  • Jun Huang,
  • Dong Fang,
  • Ting Liu

摘要

The regressed arms of reversed replication forks exhibit structural similarities to one-ended double-stranded breaks and need to be protected against uncontrolled nucleolytic degradation. Here, we identify MSANTD4 (Myb/SANT-like DNA-binding domain-containing protein 4), a functionally uncharacterized protein that uniquely counters the replication protein A (RPA)–Bloom (BLM)/Werner syndrome helicase (WRN)–DNA replication helicase/nuclease 2 (DNA2) complex to safeguard reversed replication forks from detrimental degradation, independently of the breast cancer susceptibility proteins (BRCA1/2)–DNA repair protein RAD51 pathway. MSANTD4 specifically interacts with the junctions between single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in DNA substrates harboring a 3′ overhang, which resemble the structural features of regressed arms processed by WRN–DNA2. This DNA-binding capability allows MSANTD4 to accumulate at reversed forks, strategically antagonizing the RPA–BLM/WRN–DNA2 complex by impeding its access to the ssDNA–dsDNA junction of the regressed arms. Loss of MSANTD4 exacerbates genome instability induced by replication stress in BRCA1/2-deficient cells. Our findings unveil a collaborative defense mechanism orchestrated by MSANTD4 and BRCA1/2–RAD51, effectively counteracting nucleolytic attacks on the regressed arms and synergistically preserving the integrity of reversed forks.