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

Alex Lyakhovich,Maria Castella,Andres Castellanos,Jordi Surralles,Jeffrey D Parvin,Maria Ramirez,Amanda M Simons

doi:10.1186/2041-9414-2-4

Abstract

BackgroundFanconi anemia (FA) is a rare autosomal recessive syndrome characterized by developmental abnormalities, progressive bone marrow failure, and predisposition to cancer. The key FA protein FANCD2 crosstalks with members of DNA damage and repair pathways that also play a role at telomeres. Therefore, we investigated whether FANCD2 has a similar involvement at telomeres.ResultsWe 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.ConclusionsFANCD2 binding and inhibiting tankyrase-1PARsylation at telomeres may provide an additional step within the FA pathway for the regulation of genomic integrity.

Highlights

Fanconi anemia (FA) is a rare autosomal recessive syndrome characterized by developmental abnormalities, progressive bone marrow failure, and predisposition to cancer
FANCD2 binding and inhibiting tankyrase-1PARsylation at telomeres may provide an additional step within the FA pathway for the regulation of genomic integrity
FANCD2 binds to telomeric DNA in vitro We attempted to find a novel role for FANCD2 at telomeres and tested whether FANCD2 might bind to telomeric DNA sequence in vitro

Summary

Introduction

Fanconi anemia (FA) is a rare autosomal recessive syndrome characterized by developmental abnormalities, progressive bone marrow failure, and predisposition to cancer. The key FA protein FANCD2 crosstalks with members of DNA damage and repair pathways that play a role at telomeres. Fanconi anemia (FA) is a rare recessive disorder associated with chromosomal fragility, aplastic anemia, congenital abnormalities and a predisposition to cancer [1,2]. At least 14 FA genes are known to exist, each of them representing a different FA subtype [5,6,7] 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]. The ends of chromosomes, consist of TTAGGG tandem repeats (in mammals) forming a

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