TGF-β Pathway Inhibition Signals New Hope for Fanconi Anemia Hemanth Tummala, Inderjeet Dokal  Cell Stem Cell  Volume 18, Issue 5, Pages 567-568 (May 2016) DOI: 10.1016/j.stem.2016.04.008 Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 1 TGF-β Inhibition Signals Faithful Fanconi Anemia DNA Repair Pathway In normal cells interstrand DNA cross-links initiate the FA DNA repair pathway. FA core complex, FA-ID2 complex, and homologous recombination (HR) proteins act in concert to regulate HR activity. FANCD2, upon activation by the FA core complex, inhibits TGF-β signaling by repressing SMAD3 transcription (Zhang et al., 2016). This ensures faithful DNA repair through increase in HR activity and concomitant decrease in non-homologous end joining (NHEJ). Currently it is not known whether increased TGF-β signaling (as occurs in cells harboring biallelic FA mutations) inhibits HR proteins directly or indirectly and this is therefore depicted with the red dotted line. It also remains unknown which of the FANCD2 interactions (TGF-β pathway or the HR proteins) is more critical in FA cells. However, as shown by Zhang et al., in FA cells, TGF-β inhibition promotes HR DNA repair and improves HSPC survival. Cell Stem Cell 2016 18, 567-568DOI: (10.1016/j.stem.2016.04.008) Copyright © 2016 Elsevier Inc. Terms and Conditions