ArticleProceedings of the National Academy of Sciences of the United States of America2017
FANCM, BRCA1, and BLM cooperatively resolve the replication stress at the ALT telomeres.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 98 papers.
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Who cites it
98 citing papers in PubMed, 145 citations in OpenAlex.
- Twisting the End Game: How Telomere Chromatin Modifications Shape Telomere Maintenance.Aging cell · 2026Review
- SMARCAL1 is a candidate therapeutic target for ALT-positive tumors.Genes & development · 2026Article
- Tumorigenic p53N236S balances aging and tumorigenesis via regulating DREAM/MMB and downstream telomere DNA replication pathways.Journal of molecular cell biology · 2026Article
- SLX4IP limits replication stress globally and at ALT telomeres.The EMBO journal · 2026Article
- Review
- Highly mutagenic copying of telomeric circles promotes ALT establishment.Nature communications · 2026Article
- CHAMP1 complex promotes heterochromatin assembly and reduces replication stress.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Photosensitive composite nanoparticles adsorbing p-shDrug delivery · 2025Article
- Large-scale drug sensitivity, gene dependency, and proteogenomic analyses of telomere maintenance mechanisms in cancer cells.Nature communications · 2025Article
- The alternative lengthening of telomeres pathway through a DNA repair lens: mechanism and therapeutic opportunities.NAR cancer · 2025Review
- Mechanisms and genomic implications of break-induced replication.Nature structural & molecular biology · 2025Review
- Distinct mechanisms underlying extrachromosomal telomere DNA generation in ALT cancers.Nucleic acids research · 2025Article
- TRIM24 directs replicative stress responses to maintain ALT telomeres via chromatin signaling.Molecular cell · 2025Article
- Targeting FANCM by antisense oligonucleotides in ALT-positive cancers.Molecular therapy. Nucleic acids · 2025Article
- Targeting FANCM using the antisense oligonucleotides to treat the ALT-positive cancers.Molecular therapy. Nucleic acids · 2025Article
- SLX4IP acts in parallel to FANCM to limit BLM-dependent replication stress at ALT telomeres.bioRxiv : the preprint server for biology · 2025Article
- Multiple functions of the ALT favorite helicase, BLM.Cell & bioscience · 2025Review
- Elevated reactive oxygen species can drive the alternative lengthening of telomeres pathway in ATRX-null cancers.Nucleic acids research · 2025Article
- The single-stranded DNA-binding factor SUB1/PC4 alleviates replication stress at telomeres and is a vulnerability of ALT cancer cells.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- BRCA1 and BRCA2: from cancer susceptibility to synthetic lethality.Genes & development · 2025Review
38 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
In the mammalian genome, certain genomic loci/regions pose greater challenges to the DNA replication machinery (i.e., the replisome) than others. Such known genomic loci/regions include centromeres, common fragile sites, subtelomeres, and telomeres. However, the detailed mechanism of how mammalian cells cope with the replication stress at these loci/regions is largely unknown. Here we show that depletion of FANCM, or of one of its obligatory binding partners, FAAP24, MHF1, and MHF2, induces replication stress primarily at the telomeres of cells that use the alternative lengthening of telomeres (ALT) pathway as their telomere maintenance mechanism. Using the telomere-specific single-molecule analysis of replicated DNA technique, we found that depletion of FANCM dramatically reduces the replication efficiency at ALT telomeres. We further show that FANCM, BRCA1, and BLM are actively recruited to the ALT telomeres that are experiencing replication stress and that the recruitment of BRCA1 and BLM to these damaged telomeres is interdependent and is regulated by both ATR and Chk1. Mechanistically, we demonstrated that, in FANCM-depleted ALT cells, BRCA1 and BLM help to resolve the telomeric replication stress by stimulating DNA end resection and homologous recombination (HR). Consistent with their roles in resolving the replication stress induced by FANCM deficiency, simultaneous depletion of BLM and FANCM, or of BRCA1 and FANCM, leads to increased micronuclei formation and synthetic lethality in ALT cells. We propose that these synthetic lethal interactions can be explored for targeting the ALT cancers.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.