Fanconi anemia protein FANCD2 inhibits TRF1 polyADP-ribosylation through tankyrase1-dependent manner

We reveal that FANCD2 may perform a novel function separate to the FANCD2/BRCA pathway. This function includes FANCD2 interaction with one of the telomere components, the PARP family member tankyrase-1. Moreover, FANCD2 inhibits tankyrase-1 activity in vitro. In turn, FANCD2 deficiency increases the polyADP-ribosylation of telomere binding factor TRF1.FANCD2 binding and inhibiting tankyrase-1PARsylation at telomeres may provide an additional step within the FA pathway for the regulation of genomic integrity.Fanconi anemia (FA) is a rare recessive disorder associated with chromosomal fragility, aplastic anemia, congenital abnormalities and a predisposition to cancer [1,2]. Cells from FA patients exhibit hypersensitivity to DNA cross-linking agents suggesting the role of FA proteins in the repair of damaged DNA [3,4]. Currently, at least 14 FA genes are known to exist, each of them representing a different FA subtype [5-7]. Although they have very few similarities, the encoded FA proteins cooperate in a common FA/BRCA pathway by forming several complexes, where the activation of a key FA protein FANCD2 (and FANCI) seems to orchestrate the cascade of events in response to DNA damage [8,9].FA proteins crosstalk with several proteins involved in both DNA damage response and telomere regulation [10-13]. Telomeres, the ends of chromosomes, consist of TTAGGG tandem repeats (in mammals) forming a T-loop structure and a 3' G-rich single-stranded overhang that invades the telomeric tracts forming a D loop [14-18]. In most human somatic cells telomeres undergo shortening with each cycle of cell division due to what is known as the "end-replication problem" [19,20]. To prevent such shortening, a specialized enzyme called telomerase serves to maintain telomere length [21]. In normally dividing somatic cells telomerase is insufficiently active to compensate for telomere shortening and telomeres undergo attrition with each round of cell division. In turn, telomeres in cancer cells