Fanconi anemia proteins, including FANCD2, are an emerging therapeutic target in cancer [6] Fanconi anemia is a disorder with a recessive Mendelian pattern of inheritance characterized by chromosomal instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair.
The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex.
[16] Humans with a FANCD deficiency display hypogonadism, male infertility, impaired spermatogenesis, and reduced female fertility.
[14] FANCD2 mutant mice exhibit chromosome mis-pairing during the pachytene stage of meiosis and germ cell loss.
[17] Lung squamous tumors express high levels of FANCD2 and members of Fanconia anemia pathway.
Recombinational repair of DNA double-strand damage - some key steps.
ATM
(ATM) is a
protein kinase
that is recruited and activated by
DNA double-strand breaks
. DNA double-strand damages also activate the
Fanconi anemia core complex
(FANCA/B/C/E/F/G/L/M).
[
7
]
The FA core complex
monoubiquitinates
the downstream targets FANCD2 and FANCI.
[
8
]
ATM activates (phosphorylates)
CHEK2
and FANCD2
[
9
]
CHEK2 phosphorylates BRCA1.
[
10
]
Ubiquinated FANCD2 complexes with
BRCA1
and
RAD51
.
[
11
]
The PALB2 protein acts as a hub,
[
12
]
bringing together BRCA1, BRCA2 and RAD51 at the site of a DNA double-strand break, and also binds to RAD51C, a member of the RAD51 paralog complex
RAD51B
-
RAD51C
-
RAD51D
-
XRCC2
(BCDX2). The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites.
[
13
]
RAD51
plays a major role in
homologous recombinational
repair of DNA during double strand break repair. In this process, an ATP dependent DNA strand exchange takes place in which a single strand invades base-paired strands of homologous DNA molecules. RAD51 is involved in the search for homology and strand pairing stages of the process.