Functional interaction between Fanconi anemia and mTOR pathways during stalled replication fork recovery

Abstract

Fanconi anemia (FA) is a multi-gene genomic instability disorder characterized by cancer predisposition. Clinically, FA patients are diagnosed with bone marrow failure as well as different types of cancer, mainly acute myeloid leukemia and solid tumors. FA genes encode for DNA damage repair proteins. One of the consequences of cellular exposure to DNA damaging agents is that the DNA replication stalls. Once damaged DNA is repaired, replication needs to restart. We have previously demonstrated that FA proteins work in concert with other FA as well as non-FA proteins to mediate restart of stalled replication forks. Previous studies strongly suggest a connection between the FA protein FANCD2 and a non-FA protein named mechanistic target of rapamycin (mTOR). mTOR is a central regulator of critical cellular functions such as cellular growth, proliferation and survival, transcription, protein and nucleotide synthesis, and autophagy. mTOR was shown to regulate DNA damage through NF-kB-mediated FA pathway. A recent study further showed that mTOR is involved in actin-dependent DNA replication fork restart, strongly suggesting possible roles in the FA DNA repair pathway. In this study, we demonstrate that mTOR physically interacts with FANCD2 during DNA damage or replication stress. We further show that mTOR cooperates with FANCD2 to provide cellular stability after replication fork stalling, and that mTOR-FANCD2 pathways work in concert to mediate stalled replication fork restart. mTOR also shares the function of FANCD2 in preventing nucleolytic degradation of the nascent DNA strands at the stalled replication forks. Taken together, this study unravels a novel functional cross-talk between two important mechanisms: mTOR and FA DNA repair pathways that together ensure genomic stability during proliferation.