ArticleGenes & development2025
MRN-CtIP, EXO1, and DNA2-WRN/BLM act bidirectionally to process DNA gaps in PARPi-treated cells without strand cleavage.
Article in Genes & development, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Replication stress in cancer: origins, consequences and therapeutic opportunities.Nature reviews. Cancer · 2026Review
- Suppression of transcription-replication conflicts by sequence-coordinated actions of TRDMT1 and MutLα.Nature communications · 2026Article
- Lesions initiating spontaneous mitotic crossover are minimally subject to non-homologous end joining.bioRxiv : the preprint server for biology · 2026Article
- Replication protein A protects lagging strand gaps, restricting PARP inhibitor-induced synthetic lethality in BRCA1-deficient tumors.Nucleic acids research · 2026Article
- A phosphorylation switch at MRE11 links ATM-ATR and calcium signaling to safeguard stalled replication fork stability.Research square · 2026Article
- Understanding single stranded DNA gaps: from formation to fate.The Biochemical journal · 2026Review
- The bacterial MRE11-RAD50 and DNA2-WRN homologs process replication forks at distinct and separate loci on the chromosome.FEBS letters · 2026Article
- The expanding roles of homologous recombination proteins in genome stability.The EMBO journal · 2026Review
- Fork Reversal Safeguards Epigenetic Inheritance During Replication Stress.Research square · 2026Article
- Rad51 determines pathway usage in post-replication repair.Nature communications · 2026Article
- How DNA secondary structures drive replication fork instability.DNA repair · 2025Review
- Mechanistic insights into the monotherapy and combination potential of FEN1 inhibition in cancer therapy.Nucleic acids research · 2025Article
- RAD51 is chromatin enriched and targetable in BRCA1-deficient cells.Molecular cell · 2025Article
- Automated machine learning profiling with MAP-HR for quantifying homologous recombination foci in patient samples.NAR cancer · 2025Article
- The DNA replication checkpoint targets the kinetochore to reposition DNA structure-induced replication damage to the nuclear periphery.Cell reports · 2025Article
- Comprehensive review on Fanconi anemia: insights into DNA interstrand cross-links, repair pathways, and associated tumors.Orphanet journal of rare diseases · 2025Review
- DNA repair and the contribution to chemotherapy resistance.Genome medicine · 2025Review
- Gap resection matters in BRCA mutant cancer.Genes & development · 2025Article
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Abstract
Single-stranded DNA (ssDNA) gaps impact genome stability and PARP inhibitor (PARPi) sensitivity, especially in BRCA1/2-deficient tumors. Using single-molecule DNA fiber analysis, electron microscopy, and biochemical methods, we found that MRN, CtIP, EXO1, and DNA2-WRN/BLM resect ssDNA gaps through a mechanism different from their actions at DNA ends. MRN resects ssDNA gaps in the 3'-to-5' direction using its pCtIP-stimulated exonuclease activity. Unlike at DNA ends, MRN does not use its endonucleolytic activity to cleave the 5'-terminated strand flanking the gap or the ssDNA. EXO1 and DNA2-WRN/BLM specifically resect the 5' end of the gap independent of MRN-CtIP. This resection process alters ssDNA gap repair kinetics in BRCA1-proficient and -deficient cells. In BRCA1-deficient cells treated with PARPis, excessive resection results in larger ssDNA gaps, hindering their repair and leading to DNA breaks in subsequent cell cycle stages due to ssDNA gaps colliding with DNA replication forks. These findings broaden our understanding of the role of human nucleases in DNA metabolism and have significant implications for defining the mechanisms driving PARPi sensitivity in BRCA-deficient tumors.
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