Coregulation of FANCA and BRCA1 in human cells

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.

Maintenance of genome stability by Fanconi anemia proteins

“…On the other hand, hypomethylation of FANCA promoters in squamous cell carcinoma of larynx (LSCC) cells has also been shown [ 160 ], which could mean that higher expression levels of these proteins contribute to oncogenic potential. Consistent with this, FANCA expression is up-regulated in basal breast tumors compared with non-basal breast tumors, and has higher expression levels in RB1 -mutated retinoblastomas than MYCN -amplified retinoblastomas [ 161 ].…”

miR-142-3p attenuates breast cancer stem cell characteristics and decreases radioresistance in vitro

“…Indeed, a coregulation of BRCA1 and BRCA2 has been previously described. 45 BRCA1 is not a predicted target, which supports this assumption.…”

Analysis of polymorphisms in genes associated with the FA/BRCA pathway in three patients with multiple primary malignant neoplasms

“…BRCA genes are well-known tumour suppressor genes and mutations in this family of genes can result in high susceptibility to breast cancer and ovarian cancer. BRCA1 negatively regulates the cell cycle [20], and it is known that BRCA and FANCA function together [21]. Previous studies showed that FANCJ and BACH1 (BRCA1-associated C-terminal helicase) [22], FANCD1 and BRCA2, FANCN and PALB2, FANCJ and BRIP1 are the same proteins [23], demonstrating that FA genes and the BRCA gene family are strongly related.…”