Advances in the Understanding of Fanconi Anemia Complementation Group D2 Protein (FANCD2) in Human Cancer

Abstract

Fanconi anemia (FA) is a rare human genetic disease, resulting from dysfunction in any of 17 known complementation proteins: FANC-A, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q & S, and other unknowns. Besides the severe bone marrow failure, an extremely high incidence of cancer as well as many other clinic symptoms associated with FA patients, FA cells are known of insufficiency in homologous recombination, DNA mismatch repair, nucleotide excision repair, translesion DNA synthesis, and other molecular defects, leading to genome instability. Those similar molecular and cellular/tissue features show that all FA proteins function in one common signaling pathway, namely, the FA pathway. The monoubiquitination of FANCD2 is the central step of the FA pathway activation upon DNA damage or during DNA replication. The molecular functions of FANCD2 emerge as a very attractive filed of investigation in cancer research. Herein, we review the recent progresses in FANCD2 functions at these rapidly progressed aspects.

Overlooked FANCD2 variant encodes a promising, portent tumor suppressor, and alternative polyadenylation contributes to its expression

“…Swift [26]. However, in patients without FA, these roles were only empirically demonstrated since 2010 by the work we conducted [48–52]. With the hidden identity of a more potent central player, the relatively shorter form of FANCD2, V1, has been, unfortunately, recognized as the only representative of the FA pathway for decades.…”

Next-generation DNA sequencing identifies mutated FANCD2 Gene as a novel Biomarker for monitoring early disease progression and timely therapeutic interventions in advanced phase Chronic Myeloid Leukemia patients

“…In early studies, Curcumin, Wortmannin, H-9, and Alsterpaullone were found to inhibit FANCD2 by apoptosis through the NFκB pathway (Chirnomas, 2006). A study further assessed monoketone analogues of Curcumin and found that EF24 was more specific and active against monoubiquitination of FANCD2 (Shen et al 2015). Lastly, a recent study has identified CU2 as a compound that shows potential biochemical ubiquitylation selectivity and activity against the FA pathway (Cornwell, 2019).…”

“…In addition, there have been reports that linked cancer incidence with FA pathway mutations (Shen, 2015). The previously mentioned mutations were reported to cause FA bone marrow failure.…”

Next-Generation DNA Sequencing Identifies Mutated FANCD2 Gene as a Novel Biomarker for Monitoring Early Disease Progression and Timely Therapeutic Interventions in Advanced Phase Chronic Myeloid Leukemia Patients

“…In early studies, Curcumin, Wortmannin, H-9, and Alsterpaullone were found to inhibit FANCD2 by apoptosis through the NFκB pathway (Chirnomas, 2006). A study further assessed monoketone analogues of Curcumin and found that EF24 was more specific and active against monoubiquitination of FANCD2 ( Shen et al 2015). Lastly, a recent study has identified CU2 as a compound that shows potential biochemical ubiquitylation selectivity and activity against the FA pathway (Cornwell, 2019).…”