Regulation of the Fanconi Anemia DNA Repair Pathway by Phosphorylation and Monoubiquitination

Abstract

The Fanconi anemia (FA) DNA repair pathway coordinates a faithful repair mechanism for stalled DNA replication forks caused by factors such as DNA interstrand crosslinks (ICLs) or replication stress. An important role of FA pathway activation is initiated by monoubiquitination of FANCD2 and its binding partner of FANCI, which is regulated by the ATM-related kinase, ATR. Therefore, regulation of the FA pathway is a good example of the contribution of ATR to genome stability. In this short review, we summarize the knowledge accumulated over the years regarding how the FA pathway is activated via phosphorylation and monoubiquitination.

Keywords: ATM; ATR; DNA repair; Fanconi anemia; interstrand crosslink; phosphorylation; ubiquitination.

Figure 1

The 22 FANC proteins are classified into four groups according to their proposed functions in ICL repair. Recent cryo-electron microscopy (EM) studies have determined the fine structure of the FA core complex (group 2), which comprises nine proteins organized in three subcomplexes: BL100 (composed of two copies of FANCB, FANCL, and FAAP100), CEF (composed of a single copy of FANCC, FANCE, and FANCF), and AG20 (composed of two copies of FANCA and FANCG and 1 or 2 copies of FAAP100) [12,13,14,15]. Unhooking: ICL removal by cutting the activity of the nucleases.

Figure 2

Schematic diagram of human FANCI, indicating the six putative phosphorylation sites within the S/TQ cluster domain. K523 is the monoubiquitination site of the human FANCI.

Figure 3

Proposed activation model of the FANCD2–FANCI complex by phosphorylation and monoubiquitination. See details in the text. This model was constructed according to the results of Tan et al. [28,30].