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<p>Break-induced replication (BIR) is a primary homologous recombination pathway for repairing one-ended double-strand DNA breaks, including those arising from collapsed replication forks and eroded telomeres. BIR frequently leads to loss of heterozygosity, genetic mutations, and gross chromosomal rearrangements, all hallmarks of cancer. Here, we conducted a genome-wide screen that allowed us to identify and validate the involvement of 33 novel yeast genes in BIR. We report that, while DNA damage and spindle checkpoint machineries are both required to delay nuclear division and provide adequate time for BIR to complete, the spindle position checkpoint is required to coordinate between nuclear division and cytokinesis. Furthermore, we show that two nucleopore proteins play a sequential role during BIR: Nup84 acts before DNA synthesis, while Nup188 functions later to support repair completion. Given the conservation of BIR between yeast and humans and the role of BIR in cancer development, human homologs of the identified BIR proteins may represent promising targets for anti-cancer therapeutics.</p>

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Genome-wide screen reveals dependence of break induced replication on several distinct checkpoints

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月15日

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  • Liping Liu,
  • Rosemary S. Lee,
  • Jerzy M. Twarowski,
  • Timothy Emagbetere,
  • Jessie Thomas,
  • Jacob M. Wells,
  • Gabriel J. Seuferer,
  • Kirill Lobachev,
  • Anna Malkova

摘要

Break-induced replication (BIR) is a primary homologous recombination pathway for repairing one-ended double-strand DNA breaks, including those arising from collapsed replication forks and eroded telomeres. BIR frequently leads to loss of heterozygosity, genetic mutations, and gross chromosomal rearrangements, all hallmarks of cancer. Here, we conducted a genome-wide screen that allowed us to identify and validate the involvement of 33 novel yeast genes in BIR. We report that, while DNA damage and spindle checkpoint machineries are both required to delay nuclear division and provide adequate time for BIR to complete, the spindle position checkpoint is required to coordinate between nuclear division and cytokinesis. Furthermore, we show that two nucleopore proteins play a sequential role during BIR: Nup84 acts before DNA synthesis, while Nup188 functions later to support repair completion. Given the conservation of BIR between yeast and humans and the role of BIR in cancer development, human homologs of the identified BIR proteins may represent promising targets for anti-cancer therapeutics.