Focal Point of Fanconi Anemia Signaling

Abstract

Among human genetic diseases, Fanconi Anemia (FA) tops all with its largest number of health complications in nearly all human organ systems, suggesting the significant roles played by FA genes in the maintenance of human health. With the accumulated research on FA, the encoded protein products by FA genes have been building up to the biggest cell defense signaling network, composed of not only 22+ FA proteins but also ATM, ATR, and many other non-FA proteins. The FA D2 group protein (FANCD2) and its paralog form the focal point of FA signaling to converge the effects of its upstream players in response to a variety of cellular insults and simultaneously with downstream players to protect humans from contracting diseases, including aging and cancer. In this review, we update and discuss how the FA signaling crucially eases cellular stresses through understanding its focal point.

Keywords: DNA damage response; fanconi anemia; genetic disease; genome stability.

Figure 1

Schematic Representation of Focal Point of the FA Signaling Network. FA signaling is centered by FA group D2 protein (FANCD2) and its paralog (FANCI), which form the focal point of FA signaling. Both upstream and downstream of this focal point contain an undefined number of players. The focal point converges the effects of upstream players in response to a variety of cellular insults and works simultaneously with downstream players to guard genome stability and to ultimately prevent humans from contracting a variety of diseases, including aging and cancer. Further, each player of DDR/FA signaling (1) is working relatively in a phase of DNA damage responses. For example, FANCD2 and FANCI may mainly act as transducers; however, they can also be sensors or effectors as the dotted bold lines indicate at the right.

Figure 2

Illustrating functional roles of FA signaling with a relatively defined focal point.

Figure 3

Schematic Outline of a Putative Evolutionary Path for the Focal Point of DDR/FA Signaling across Different Species. In bacteria, the homolog of FANCD2 may act as a sensor, transducer, and/or effector in response to genotoxic stresses. However, it receives a helper of FANCI and a regulator of FANCL in silkworm upon coupling with a variety of insults. FANCL, here, may act relatively more as a sensor. In vertebrate, FANCD2 and FANCI appear to be totally centered, which work in concert with many others to form a very complicated cellular defense signaling network.