The Mre11 complex, composed of RAD50, NBS1 and MRE11, has an essential role in the maintenance of genomic integrity and preventing cells from malignancy. Here we report the association of three Mre11 complex mutations with hereditary breast cancer susceptibility, studied by using a case-control design with 317 consecutive, newly diagnosed Northern Finnish breast cancer patients and 1000 geographically matched healthy controls (P = 0.0004). RAD50 687delT displayed significantly elevated frequency in the studied patients (8 out of 317, OR 4.3, 95% CI 1.5-12.5, P= 0.008), which indicates that it is a relatively common low-penetrance risk allele in this cohort. Haplotype analysis and the screening of altogether 512 additional breast cancer cases from Sweden, Norway and Iceland suggest that RAD50 687delT is a Finnish founder mutation, not present in the other Nordic cohorts. The RAD50 IVS3-1G>A splicing mutation leading to translational frameshift was observed in one patient, and the NBS1 Leu150Phe missense mutation affecting a conserved residue in the functionally important BRCA1 carboxy-terminal (BRCT) domain in two patients, both being absent from 1000 controls. Microsatellite marker analysis showed that loss of the wild-type allele was not involved in the tumorigenesis in any of the studied mutation carriers, but they all showed increased genomic instability assessed by cytogenetic analysis of peripheral blood T-lymphocytes (P = 0.006). In particular, the total number of chromosomal rearrangements was significantly increased (P = 0.002). These findings suggest an effect for RAD50 and NBS1 haploinsufficiency on genomic integrity and susceptibility to cancer.

The potential atmospheric impact of constructed wetlands (CWs) should be examined as there is a worldwide increase in the development of these systems. Fluxes of N(2)O, CH(4), and CO(2) have been measured from CWs in Estonia, Finland, Norway, and Poland during winter and summer in horizontal and vertical subsurface flow (HSSF and VSSF), free surface water (FSW), and overland and groundwater flow (OGF) wetlands. The fluxes of N(2)O-N, CH(4)-C, and CO(2)-C ranged from -2.1 to 1000, -32 to 38 000, and -840 to 93 000 mg m(-2) d(-1), respectively. Emissions of N(2)O and CH(4) were significantly higher during summer than during winter. The VSSF wetlands had the highest fluxes of N(2)O during both summer and winter. Methane emissions were highest from the FSW wetlands during wintertime. In the HSSF wetlands, the emissions of N(2)O and CH(4) were in general highest in the inlet section. The vegetated ponds in the FSW wetlands released more N(2)O than the nonvegetated ponds. The global warming potential (GWP), summarizing the mean N(2)O and CH(4) emissions, ranged from 5700 to 26000 and 830 to 5100 mg CO(2) equivalents m(-2) d(-1) for the four CW types in summer and winter, respectively. The wintertime GWP was 8.5 to 89.5% of the corresponding summertime GWP, which highlights the importance of the cold season in the annual greenhouse gas release from north temperate and boreal CWs. However, due to their generally small area North European CWs were suggested to represent only a minor source for atmospheric N(2)O and CH(4).

A pproximately 5-10% of all breast and ovarian cancers are thought to arise from a hereditary predisposition to the disease, 1 BRCA1 and BRCA2 being the most important susceptibility genes.2 3 Genomic alterations in BRCA1 are found in 40-50% of families with a high incidence of breast cancer (six or more cases), and in a majority (75-80%) of the families that display both breast and ovarian cancers.4 5 However, a significant portion of genetic aberrations predisposing to these cancers, especially in relatively small risk families, still remains unexplained.6 7 BRCA1 interacts with a variety of proteins and is involved in multiple cellular processes including DNA repair, transcription, and checkpoint control. [8][9][10] In attempts to identify new breast and ovarian cancer susceptibility genes, much research has focused on BRCA1 associated proteins.BARD1 was originally identified through its interaction with BRCA1, with which it has a closely related domain structure.11 Both proteins possess an N-terminal RING finger motif and two BRCA1 C-terminal (BRCT) domains present in numerous proteins involved in DNA repair and cell cycle regulation. 11The functionally important BARD1/BRCA1 heterodimer formation is mediated by the RING finger motifs and has also been shown to markedly increase the stability of both proteins.11-13 The finding of breast cancer associated mutations within the RING finger domain of BRCA1, disrupting BRCA1/BARD1 interaction, 11 14 and the occurrence of BARD1 missense mutations in breast cancer patients, [15][16][17] implies participation of BARD1 in BRCA1 mediated tumour suppression. BARD1, unlike BRCA1, also contains a centrally located sequence of three ankyrin repeats 11 that are found in many proteins involved in transcriptional regulation. 18Colocalisation of BARD1 with BRCA1 and RAD51 in response to DNA damage indicates a role in DNA repair, 19 20 which is supported by the recent observation of BARD1 participation along with BRCA1 in homology directed repair of chromosome breaks. 21 Furthermore, interaction between the BARD1/BRCA1 heterodimer and cleavage stimulation factor subunit 1 (CSTF1, also called CstF-50) represses the polyadenylation machinery, presumably to prevent inappropriate mRNA processing at sites of DNA repair.22 23 The significance of BARD1/BRCA1 collaboration has also been emphasised by studies of its ubiquitin ligase activity that might contribute to tumour suppression and other biological functions of BRCA1. 24 In vivo substrates for the ubiquitination are not yet known, but involvement of the RNA polymerase-2 holoenzyme has been proposed. 25 BARD1 also regulates the subcellular localisation of BRCA1, both by translocating BRCA1 into the nucleus and by inhibiting its nuclear export. 26 The suggested role in TP53 dependent apoptotic signalling 27 and interaction with the ankyrin repeats of proto-oncoprotein BCL3, thereby possibly modulating the activity of transcription factor NFKB, 28 represent BRCA1 independent functions of BARD1. In addition, the effects of reduced...

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