*2.3. Fanconi Anemia*

Fanconi anemia (FA) is a disorder caused by the genetic inactivation of crosslink repair. FA is characterized by abnormal development, bone marrow failure, hypogonadism, and marked cancer susceptibility. Autosomal recessive mutations in any one of 20 genes (*FANCA* to *FANCQ*) result in this genetic disorder, and collectively, the FANC gene products function in a FA−DNA crosslink repair pathway [99]. Several of the FANC genes form a large monoubiquitination complex (FA core complex). Ubiquitin conjugating enzyme E2 T (UBE2T, also called FANCT) and E3 ligase FA complementation group L (FANCL) are key enzymes in the FA core complex and are mutated in di fferent subtypes of FA, causing FA-T and FA-L respectively [56,57] (Table 1).

Several animal models were generated to study the disease. *Ube2t* knockout in zebrafish leads to hypersensitivity to DNA damage and reversion of female-to-male sex [99], reflecting the hypogonadism phenotype occurring in FA patients. *Fancl* knockout in mice leads to decrease of fertility and defects in the proliferation of germ cells. Bone marrow cells isolated from the *Fancl* knockout mice were also hypersensitive to DNA crosslinking agent, mitomycin C [57].

The hallmark of FA is a high frequency of chromosomal aberrations caused by defects in DNA repair and hypersensitivity to DNA crosslinking agents in cells isolated from patients [100]. When DNA replication is stalled, the FA core complex is activated and monoubiquitinates the FA group D2 (FANCD2) and FA complementation group I (FANCI) heterodimer [52]. Monoubiquitinated FANCD2/FANCI heterodimer adopts a closed conformation, creating a channel that encloses double-stranded DNA [53]. The ubiquitin residue plays a key role in this process as it acts as a covalent molecular pin to trap the complex on DNA. Moreover, monoubiquitinated FANCD2 serves as a signal to recruit to the replication fork, DNA repair proteins that contain ubiquitin-binding motifs [101], such as FA complementation group P (FANCP, also called SLX4) and FA complementation group Q (FANCQ, also called ERCC), to remove the cross-linked DNA [54,55] (Figure 1C). DNA crosslinking repair is completed when ubiquitin-specific protease 1 (USP1) reverses the monoubiquitination of FANCD2 [102–104]. Interestingly, knockout of *Usp1* in mice also recapitulates FA phenotypes, including perinatal lethality, infertility, and crosslinker hypersensitivity. Finally, FANCD2 monoubiquitination could also be mediated by the ubiquitin ligase activity of the E3 ligase BRCA1 [58]. *BRCA1* is also mutated in a subset of patients suffering from Fanconi anemia D1 (FANCD1), identifying another key ubiquitin ligase in the pathogenesis of FA [59].
