Targeting FANCD2 for therapy sensitization

The Fanconi Anemia (FA) signaling pathway is essential for the maintenance of genome integrity and cells to survive DNA interstrand crosslink (ICL) by coordinating DNA damage repair through translesion DNA synthesis (TLS), nucleotide excision repair (NER) and homologous recombination (HR). Besides ICL, the FA signaling pathway is activated by different kinds of genotoxins and plays an important role in the activation of the ATM DNA damage and ATR intra-S phase checkpoints. There are fifteen FANC genes identified in FA or FA-like patients. FA-pathway deficient cells display spontaneous DNA strand breaks under normal growth conditions and defect of DNA damage checkpoint activation in response to DNA damage or replication stress [1]. FANCD2 is the critical component of FA signaling. In response to ICL, the FA pathway activates the FA core E3 ubiquitin ligase complex, which in turn leads to monoubiquitination of FANCI and FANCD2. Monoubiquitinated FANCI-FANCD2 complex is recruited to DNA damage sites and helps endonucleases to cut both sides of ICL to generate DNA strand breaks, and promotes TLS, NER and Rad51-medated HR [2,3]. The molecular mechanisms by which FA signaling maintains genome stability, coordinates multiple DNA damage repair pathways and facilitates the activity of ATM/ATR checkpoints, remain to be determined. We have recently reported [4] that FANCD2 is required for the timely ATM-Chk2 activation in the early steps of FA signalingmediated repair of ICL-induced DNA lesions [5]. In rhabdomyosarcoma Rh30 cells, we found that during the early response to ICL FANCD2 is required for the proper phosphorylation of H2AX and hence activation of ATM, but not essential for ATR-Chk1 activation, supporting the proposed model of the function of FANCD2 in response to ICL [2,3]. The ATM DNA damage checkpoint maintains the integrity of genetic information under normal growth and cell survival in response to DNA double strand breaks [6]. Our findings suggest that FANCD2 dependent activation of the ATM checkpoint in the early response to ICL is one of the mechanisms by which FA signaling promotes genome stability under normal growth condition and cell survival in response to genotoxins. Most cancers have deregulated the PI3K and Ras signaling pathways, both of which converge on the mammalian target of rapamycin (mTOR). Molecularly targeting PI3K or Ras signaling sensitizes many cancers to radiotherapy and chemotherapy [7]. Moreover, in yeast, TOR promotes cell survival but at the cost of increased mutation rate in response to DNA damage agents [8]. We found that an mTOR kinase inhibitor sensitizes mouse rhabdomyosarcoma Rh30 tumor xenografts to ionizing radiation and cultured Rh30 cells to the bifunctional Editorial