Abstract
Fanconi anemia (FA) is a genetically heterogeneous syndrome associated with increased cancer predisposition. The underlying genes govern the FA pathway which functions to protect the genome during the S-phase of the cell cycle. While upregulation of FA genes has been linked to chemotherapy resistance, little is known about their regulation in response to proliferative stimuli. The purpose of this study was to examine how FA genes are regulated, especially in relation to the cell cycle, in order to reveal their possible participation in biochemical networks. Expression of 14 FA genes was monitored in two human cell-cycle models and in two RB1/E2F pathway-associated primary cancers, retinoblastoma and basal breast cancer. In silico studies were performed to further evaluate coregulation and identify connected networks and diseases. Only FANCA was consistently induced over 2-fold; FANCF failed to exhibit any regulatory fluctuations. Two tools exploiting public data sets indicated coregulation of FANCA with BRCA1. Upregulation of FANCA and BRCA1 correlated with upregulation of E2F3. Genes coregulated with both FANCA and BRCA1 were enriched for MeSH-Term id(s) genomic instability, microcephaly, and Bloom syndrome, and enriched for the cellular component centrosome. The regulation of FA genes appears highly divergent. In RB1-linked tumors, upregulation of FA network genes was associated with reduced expression of FANCF. FANCA and BRCA1 may jointly act in a subnetwork - supporting vital function(s) at the subcellular level (centrosome) as well as at the level of embryonic development (mechanisms controlling head circumference).Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-3-381) contains supplementary material, which is available to authorized users.
Highlights
Fanconi anemia (FA) is a rare, recessive, genetically heterogeneous, chromosomal instability disorder, characterized by developmental abnormalities, retarded growth, bone marrow failure, and a high risk for the development of cancer (Auerbach et al 2001; Alter 2003; Rosenberg et al 2003; Kutler et al 2003)
The activation of FANCD2 and FANCI coordinates the activities of FA proteins that act downstream in the pathway leading to DNA repair: FANCD1/BRCA2, FANCJ/ BRIP1, FANCN/PALB2, FANCO/RAD51C, FANCP/SLX4, FANCQ/ERCC4/XPF and XRCC2
We found a significant upregulation in retinoblastoma tumors, for the core complex members: FANCA (FC = 3.54, P = 2.32E-06), FANCC (FC = 1.48, P = 3.25E03), FANCE (FC = 1.93, P = 2.07E-02), FANCG (FC = 4.00, P = 1.52E-07), FANCL (FC = 2.65, P = 4.95E-09), FANCM (FC = 1.51, P = 2.08E-02); central players: FANCD2 (FC = 1.95, P = 4.68E-03) and FANCI (FC = 2.69, P = 1.55E-03); and for the downstream branch: FANCD1/BRCA2 (FC = 2.90, P = 4.65E-04), FANCN/PALB2 (FC = 2.18, P = 8.70E09), and BRCA1 (FC = 2.05, P = 2.13E-04) compared to healthy fetal retina
Summary
Fanconi anemia (FA) is a rare, recessive, genetically heterogeneous, chromosomal instability disorder, characterized by developmental abnormalities, retarded growth, bone marrow failure, and a high risk for the development of cancer (Auerbach et al 2001; Alter 2003; Rosenberg et al 2003; Kutler et al 2003). Fanconi anemia patient-derived cells are extremely sensitive to bifunctional alkylating or DNA interstrand cross-linking agents, such as mitomycin C and cisplatin (Ishida and Buchwald 1982; Wang 2007). The FA/ BRCA-pathway is divided into an upstream and a downstream branch in relation to the monoubiquitination of FANCD2 and FANCI, which is considered a central activating reaction. This reaction is catalyzed by the so-called core complex, which is thought to be assembled via subcomplexes. The activation of FANCD2 and FANCI coordinates the activities of FA proteins that act downstream in the pathway leading to DNA repair: FANCD1/BRCA2, FANCJ/ BRIP1, FANCN/PALB2, FANCO/RAD51C, FANCP/SLX4, FANCQ/ERCC4/XPF and XRCC2. Homozygous germ line mutations in BRCA1 can result in a Fanconi anemia-like phenotype (Domchek et al 2013; D’Andrea 2013), BRCA1 may be considered an FA-like gene whose action may be closely connected to the FA pathway
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
