Fanconi Anemia Signaling and Cancer

Abstract

The extremely high cancer incidence associated with patients suffering from a rare human genetic disease, Fanconi Anemia (FA), demonstrates the importance of FA genes. Over the course of human tumor development, FA genes perform critical tumor-suppression roles. In doing so, FA provides researchers with a unique genetic model system to study cancer etiology. Here, we review how aberrant function of the twenty-two FA genes and their signaling network contributes to malignancy. From this perspective, we will also discuss how the knowledge discovered from FA research serves basic and translational cancer research.

DNA methylation at the vicinity of the proximal polyadenylation site in FANCD2 gene involves human malignancy

“…Whether or how DNA methylation affects the center player-FANCD2 expression is rarely studied. Here, our study first documented sea-region DNA-methylation in affecting the usage of an APS in FANCD2 gene, providing a novel key to unlock in-depth insights into FA-signaling tumor-suppression functions in both FA and non-FA cells [1,2]. Additionally, corresponding translational studies over the appreciation of FA signaling remain to be pigeonholed, although evidently indicated for establishing better therapeutic strategies [8].…”

“…FANCD2 sits at the center of this signaling network serving as an important "successor" to transduce upstream FA signaling upon genotoxicants and also as a critical "savior" for completing downstream FA signaling-transduction, involving all DNA-repair mechanisms known as far [2]. While fathoming FANCD2 functional importance, we discovered an unrecognized form of FANCD2, namely FANCD2-V2 in contrast to the longknown one, FANCD2-V1 [3].…”

A new look at molecular biology of breast cancer

“…In clinic, several different tests aiming at mtBRCAs are available for helping mitigate malignant outcomes. 2 Some tests look for a specific mutant form of BRCA1 or BRCA2 that was already identified as another family member; and other tests check for the known mutations. In addition, multigene-testing utilizes next-generation sequencing to spot for harmful mutations simultaneously in many genes that are associated with an increased risk of breast cancer, including BRCA1 and BRCA2.…”

“…Such as prophylactic mastectomy and/or oophorectomy to block the breast cancer susceptibility. 2 On the other hand, mtBRCAs have also been a better prognosis for breast cancer patients treated with DNA-damage related regimens. Given such impact of mtBRCAs, we believe that many other mutated FA genes shall possess similar influences on a subject tumor, even carrying wtBRCAs.…”

“…The BRCA-encoded proteins work mostly at the downstream of the FA pathway in concert with the activated/monoubiquitinated FANCD2 and its paralog FANCI to perform the signaling-transduction and/or DNA-damage repair, enforced by checkpoint mechanisms upon a variety of genotoxic stresses. [1][2][3][4][5] Given the fact that the malfunctioned FANCD2 confers the molecular defects for more than 98% of FA cases, 1 studies on FANCD2 become increasingly attractive. It sits right at the center of the FA signaling pathway, orchestrating nearly all individual players in the FA signaling pathway.…”