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<p>RECQL4, a RecQ family helicase, is essential for DNA replication and genome stability. Mutations in RECQL4 cause severe human disorders yet we do not fully understand its functions, particularly regarding ATP-dependent helicase activity. To understand RECQL4’s functions further, we performed a genome-wide forward genetic screen using a murine model harbouring patient-like RECQL4 mutations. We identify KLHDC3, a substrate-binding subunit of the Cullin-RING ligase E3 complex, loss as the most significant rescue allele. KLHDC3 loss restores proliferation and replication in RECQL4-deficient cells by stabilizing trace levels of a truncated RECQL4 fragment containing the N-terminal 480 amino acids, lacking the helicase and C-terminal regions. This RECQL4 fragment forms after Cre-mediated recombination of the <i>Recql4</i><sup><i>fl</i></sup> allele and contains a neo-degron sequence specific for KLHDC3. Although this mechanism does not apply to human mutations, it demonstrates that minimal RECQL4 levels, without any ATPase domain/activity, are sufficient to support DNA replication. This demonstrates that RECQL4 is an essential and non-redundant regulator of DNA replication and cell viability and that this activity does not require its ATP-dependent helicase activity.</p>

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Minute amounts of helicase-deficient truncated RECQL4 are sufficient for DNA replication

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月10日

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  • Paula Armina V Buco,
  • Wilson Castillo-Tandazo,
  • Alistair M Chalk,
  • Courtney Pilcher,
  • Jessica K Holien,
  • Jörg Heierhorst,
  • Tiong Y Tan,
  • Amnon Koren,
  • Monique F Smeets,
  • Carl R Walkley

摘要

RECQL4, a RecQ family helicase, is essential for DNA replication and genome stability. Mutations in RECQL4 cause severe human disorders yet we do not fully understand its functions, particularly regarding ATP-dependent helicase activity. To understand RECQL4’s functions further, we performed a genome-wide forward genetic screen using a murine model harbouring patient-like RECQL4 mutations. We identify KLHDC3, a substrate-binding subunit of the Cullin-RING ligase E3 complex, loss as the most significant rescue allele. KLHDC3 loss restores proliferation and replication in RECQL4-deficient cells by stabilizing trace levels of a truncated RECQL4 fragment containing the N-terminal 480 amino acids, lacking the helicase and C-terminal regions. This RECQL4 fragment forms after Cre-mediated recombination of the Recql4fl allele and contains a neo-degron sequence specific for KLHDC3. Although this mechanism does not apply to human mutations, it demonstrates that minimal RECQL4 levels, without any ATPase domain/activity, are sufficient to support DNA replication. This demonstrates that RECQL4 is an essential and non-redundant regulator of DNA replication and cell viability and that this activity does not require its ATP-dependent helicase activity.