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


ABSTRACT: 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.

SUBMITTER: Xu M 

PROVIDER: S-EPMC6785246 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Xu Mafei M   Qin Jun J   Wang Leiming L   Lee Hui-Ju HJ   Kao Chung-Yang CY   Liu Dan D   Songyang Zhou Z   Chen Junjie J   Tsai Ming-Jer MJ   Tsai Sophia Y SY  

Science advances 20191009 10


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 involve  ...[more]

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