title: 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).
authors.affiliation: Department of Clinical Genetics, Section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Anneke
authors.initials: A
authors.lastname: Haitjema
authors.affiliation: Department of Clinical Genetics, Section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Berber M
authors.initials: BM
authors.lastname: Mol
authors.affiliation: Department of Clinical Genetics, Section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Irsan E
authors.initials: IE
authors.lastname: Kooi
authors.affiliation: Department of Clinical Genetics, Section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Maarten Pg
authors.initials: MP
authors.lastname: Massink
authors.affiliation: Department of Clinical Genetics, Section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Jens Al
authors.initials: JA
authors.lastname: Jørgensen
authors.affiliation: Department of Clinical Genetics, Section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Davy Ap
authors.initials: DA
authors.lastname: Rockx
authors.affiliation: Department of Clinical Genetics, Section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Rooimans
authors.affiliation: Department of Clinical Genetics, Section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Johan P
authors.initials: JP
authors.lastname: de Winter
authors.affiliation: Department of Clinical Genetics, Section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Hanne
authors.initials: H
authors.lastname: Meijers-Heijboer
authors.affiliation: Department of Clinical Genetics, Section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Joenje
authors.affiliation: Department of Clinical Genetics, Section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Josephine C
authors.initials: JC
authors.lastname: Dorsman
keywords: BRCA1; Breast cancer; FANCA; Fanconi anemia; Functional genomics; Retinoblastoma