FANCM, BRCA1, and BLM cooperatively resolve the replication stress at the ALT telomeres.

摘要: In the mammalian genome, certain genomic loci/regions pose greater challenges to DNA replication machinery (i.e., replisome) than others. Such known include centromeres, common fragile sites, subtelomeres, and telomeres. However, detailed mechanism of how cells cope with stress at these is largely unknown. Here we show that depletion FANCM, or one its obligatory binding partners, FAAP24, MHF1, MHF2, induces primarily telomeres use alternative lengthening (ALT) pathway as their telomere maintenance mechanism. Using telomere-specific single-molecule analysis replicated technique, found FANCM dramatically reduces efficiency ALT We further BRCA1, BLM are actively recruited experiencing recruitment BRCA1 damaged interdependent regulated by both ATR Chk1. Mechanistically, demonstrated that, in FANCM-depleted cells, help resolve telomeric stimulating end resection homologous recombination (HR). Consistent roles resolving induced deficiency, simultaneous leads increased micronuclei formation synthetic lethality cells. propose lethal interactions can be explored for targeting cancers.