Multifaceted Fanconi Anemia Signaling

Abstract

In 1927 Guido Fanconi described a hereditary condition presenting panmyelopathy accompanied by short stature and hyperpigmentation, now better known as Fanconi anemia (FA). With this discovery the genetic and molecular basis underlying FA has emerged as a field of great interest. FA signaling is crucial in the DNA damage response (DDR) to mediate the repair of damaged DNA. This has attracted a diverse range of investigators, especially those interested in aging and cancer. However, recent evidence suggests FA signaling also regulates functions outside the DDR, with implications for many other frontiers of research. We discuss here the characteristics of FA functions and expand upon current perspectives regarding the genetics of FA, indicating that FA plays a role in a myriad of molecular and cellular processes.

Keywords: DNA damage response; Fanconi anemia; aging; cancer; developmental defects; replication.

Figure 1. Schematic Representation of the FA Signaling Pathway

Part I) 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 other known proteins, assure the activity of ubiquitin E3 ligase for the monoubiquitination of FANCD2 and FANCI. Part II) FANCD2 and its paralog FANCI, as a central axis to connect or orchestrate the entire FA signaling pathway. Part III) downstream of Part-II, the remaining FA proteins. Monoubiquitinated FANCD2 and FANCI can be deubiquitinated by USP1, thereby inactivating the pathway. Red arrows indicate the canonical FA pathway. Ub indicates ubiquitination. Part I & III may include many others proteins, which have yet to be recognized. As such, the indefinite nature of FA signaling presents a particular challenge to translational studies utilizing the basic knowledge of FA to promote clinical understanding such as tumor resistance.

Figure 2. Deregulated FA signaling Gain of Function (GOF)

FA signaling is crucial to many cellular events in order to protect humans from diseases such aging, cancer, and severe bone marrow failure. Impaired FA signaling, however, not only loses the roles of the intact signaling pathway but also exhibits the GOF phenomenon, and promotes the clinical complications associated with FA.

Figure 3. System view on the flow of biological information that can be influenced by FA signaling at multiple levels

The flow of biological information in a system goes from DNA (genome) > RNA (transcriptome) > protein (proteome) > metabolite (metabolome). FA genes involved in the FA signaling network may be mutated and/or epigenetically modified. On the other hand, their normal transcripts can be abnormally processed or improperly translated into proteins, leading to a disordered metabolome, containing a variety of metabolites derived from multiple irregular cellular processes.