Fanconi Anemia Signaling and Cancer

Abstract

The extremely high cancer incidence associated with patients suffering from a rare human genetic disease, Fanconi anemia (FA), demonstrates the importance of FA genes. Over the course of human tumor development, FA genes perform critical tumor-suppression roles. In doing so, FA provides researchers with a unique genetic model system to study cancer etiology. Here, we review how aberrant function of the 22 FA genes and their signaling network contributes to malignancy. From this perspective, we will also discuss how the knowledge discovered from FA research serves basic and translational cancer research.

Keywords: ATM/ATR; Fanconi anemia signaling; cancer; genome instability; tumor development and resistance.

Figure 1. FA Signaling

FA signaling is composed of all signaling transductions involving one or more FA proteins. Within the FA signaling, the FA proteins (FANCA, B, C, E, F, G, L, M, T and possibly I) along with FAAPs (FAAP 20/24/100 and MHF1/2) and others, assure the activity of ubiquitin E3 ligase for the monoubiquitination of FANCD2 and FANCI. Monoubiquitinated FANCD2 and FANCI, in turn, orchestrate the downstream players, including the rest of FA proteins and other non-FA proteins to repair DNA damage via mechanisms of BER, NER, TLS, HR and NHEJ to maintain genome stability. In addition, USP1 can deubiquitinate FANCD2/I, thereby inactivating the FA-BRCA pathway. Most importantly, ATM, ATR and HHR6, together with others known (FANCM and FAAPs) or yet to identify, can act as the upstream regulators for the well-executed checkpoint responses upon DNA damage or replicative stresses. Red arrowheads indicate the canonical FA pathway. FANCM-centered sensing (upstream), possibly including FANCW modulation of RPA functions, would be a typical example in FA signaling to show pathway-independent roles.

Figure 2. ATR-FA signaling

When replication forks are stalled upon replicative stresses, FANCM-FAAP24-KLM and others can interact with the stalled replication forks to stabilize them for RPA to bind the ssDNA. The RPA complex accumulates and recruits ARTIP, but its function can be modulated by FANCW. The FA core complex facilitates the binding of RPA with ATRIP, which promotes ATR recruitment and followed by many downstream evens initiated by ATR, including the phosphorylation of FANCI that helps FANCD2 monoubiquitination. On the other hand, the RPA complex can also direct Rad17 to load the 9-1-1 complex, which in turn recruits TOPBP1, an activator of ATR. The activated ATR then phosphorylates many downstream targets including CHK1, FANCI, & others. This signaling network is themed with FA and FA-associated proteins from the very beginning to the further downstream of the signaling transduction. In this regard, ATR signaling can be named “ATR-FA signaling”.

Figure 3. Gain-of-Function of inactivated FANCD2

The activated/monoubiquitinated FANCD2 is the focus of the activated FA pathway, and 80% of FA cases show inability of FANCD2 activation/monoubiquitination. Inactivated FANCD2 not only loses the roles that activated FANCD2 plays, but also exhibits the gain of function phenomenon, and further promotes neoplastic transformation