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Nuclear receptors regulate alternative lengthening of telomeres through a novel noncanonical FANCD2 pathway.

Mafei XuJun QinLeiming WangHui-Ju LeeChung-Yang KaoDan LiuZhou SongyangJunjie ChenMing-Jer TsaiSophia Y Tsai
Published in: Science advances (2019)
Alternative lengthening of telomeres (ALT) is known to use homologous recombination (HR) to replicate telomeric DNA in a telomerase-independent manner. However, the detailed process remains largely undefined. It was reported that nuclear receptors COUP-TFII and TR4 are recruited to the enriched GGGTCA variant repeats embedded within ALT telomeres, implicating nuclear receptors in regulating ALT activity. Here, we identified a function of nuclear receptors in ALT telomere maintenance that involves a direct interaction between COUP-TFII/TR4 and FANCD2, the key protein in the Fanconi anemia (FA) DNA repair pathway. The COUP-TFII/TR4-FANCD2 complex actively induces the DNA damage response by recruiting endonuclease MUS81 and promoting the loading of the PCNA-POLD3 replication complex in ALT telomeres. Furthermore, the COUP-TFII/TR4-mediated ALT telomere pathway does not require the FA core complex or the monoubiquitylation of FANCD2, key steps in the canonical FA pathway. Thus, our findings reveal that COUP-TFII/TR4 regulates ALT telomere maintenance through a novel noncanonical FANCD2 pathway.
Keyphrases
  • dna repair
  • dna damage response
  • dna damage
  • chronic kidney disease
  • single molecule
  • single cell
  • small molecule
  • circulating tumor
  • cell free
  • genome wide