Cloning and characterization of the common fragile site FRA6F harboring a replicative senescence gene and frequently deleted in human tumors

Abstract

The common fragile site FRA6F, located at 6q21, is an extended region of about 1200 kb, with two hot spots of breakage each spanning about 200 kb. Transcription mapping of the FRA6F region identified 19 known genes, 10 within the FRA6F interval and nine in a proximal or distal position. The nucleotide sequence of FRA6F is rich in repetitive elements (LINE1 and LINE2, Alu, MIR, MER and endogenous retroviral sequences) as well as in matrix attachment regions (MARs), and shows several DNA segments with increased helix flexibility. We found that tight clusters of stem-loop structures were localized exclusively in the two regions with greater frequency of breakage. Chromosomal instability at FRA6F probably depends on a complex interaction of different factors, involving regions of greater DNA flexibility and MARs. We propose an additional mechanism of fragility at FRA6F, based on stem-loop structures which may cause delay or arrest in DNA replication. A senescence gene likely maps within FRA6F, as suggested by detection of deletion and translocation breakpoints involving this fragile site in immortal human-mouse cell hybrids and in SV40-immortalized human fibroblasts containing a human chromosome 6 deleted at q21. Deletion breakpoints within FRA6F are common in several types of human leukemias and solid tumors, suggesting the presence of a tumor suppressor gene in the region. Moreover, a gene associated to hereditary schizophrenia maps within FRA6F. Therefore, FRA6F may represent a landmark for the identification and cloning of genes involved in senescence, leukemia, cancer and schizophrenia.

Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

“…The 13q14 band, containing the RB locus, is frequently deleted in AML but rarely in ALL (19). Finally, the 6q21 band contains a site of common chromosomal fragility and is commonly deleted in hematologic malignancies (20).…”

Common fragile sites are preferential targets for HPV16 integrations in cervical tumors

“…To date, the molecular location and analysis of six CFSs have been reported in the literature (Wilke et al, 1996a;Huang et al, 1998;Mishmar et al, 1998;Krummel et al, 2000;Mangelsdorf et al, 2000;Paige et al, 2000;Arlt et al, 2002;Morelli et al, 2002). This analysis along with our initial report (Thorland et al, 2000) has determined the molecular localization of eight additional CFSs.…”

“…The 87 CFSs are distributed throughout the genome. To date, six aphidicolin-sensitive CFSs have been cloned and characterized: FRA3B, FRA7G, FRA7H, FRA16D, FRAXB, and FRA6F (Wilke et al, 1996a;Huang et al, 1998;Mishmar et al, 1998;Krummel et al, 2000;Mangelsdorf et al, 2000;Paige et al, 2000;Arlt et al, 2002;Morelli et al, 2002). The mechanistic reason for the instability of these sites is still unclear, but it is likely different from that of the RFSs since no unstable repeat sequences have been shown to be associated with CFSs.…”

FoxO3a gene is a target of deletion in mouse lung adenocarcinoma

“…CIN is an enhanced rate of chromosomal defects that serves as a source of genetic variability in cancer cells and seems to be mechanistically linked with FoxO3a loss in this study (29)(30)(31). Interestingly, the human FRA6F fragile site is located within the human FoxO3a gene (32). A characteristic of fragile sites is that they are relatively sensitive to breakage induced by carcinogens and CIN (33).…”