BACH1 517C→T transition impairs protein translocation to nucleus: A role in breast cancer susceptibility?

Abstract

Dear Sir,Recent predictions of risks of developing a complex disease based on common genetic variations using breast cancer as a model suggest that the construction and use of genetic-risk profiles may improve the efficacy of population-based programs of intervention. 1 However, the identification of genes, alleles or haplotypes predisposing to complex diseases including breast cancer has been difficult to accomplish, despite the existence of a significant proportion of familial cases of breast cancer that cannot be attributed to BRCA1 or BRCA2 mutations. 2,3 A major obstacle has been an insufficient statistical power of allelic association, linkage and population studies and a lack of functional assays for candidate allelic variants. Although common genetic variants are thought to confer a risk of breast cancer through multiplicative effects of a number of predisposing alleles, 1 the significance of rare allelic polymorphisms has been particularly difficult to address because a prohibitive sample size would be required for allelic association studies.DNA helicases represent an important group of enzymes implicated in DNA repair, replication, recombination and transcription. 4 Deficiencies of DNA helicases have been linked to cancer predisposition and premature aging as mutations in genes encoding the RecQ DNA helicases have been associated with cancer-predisposing syndromes, such as BLM in Bloom's syndrome, WRN in Werner's syndrome and RecQ4 in Rothmund-Thomson's syndrome. 4,5 In addition, mutations in 2 DNA helicase-encoding genes, XPB and XPD, have been linked to xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy, 6 and polymorphisms in XPD have been associated with a risk of developing basal cell carcinomas and melanomas. 7 A recently described nuclear DNA helicase BACH1, 8 which has a high-sequence homology to a UV-induced protein SUVi at both protein and DNA levels, 9 has been implicated in the repair of double-strand DNA breaks through its direct interaction with BRCA1. Two germline missense mutations were found in 65 breast cancer patients lacking BRCA1 and BRCA2 alterations, 8 suggesting that BACH1 may be a breast cancer susceptibility gene. However, a follow-up study reported no mutations in the germline of 29 multiple-case breast cancer families with positive nonparametric linkage scores to short tandem repeats flanking the BACH1 locus at 17q and of 95 unrelated individuals with familial breast cancer who had no detectable mutation in BRCA1 and BRCA2. 10 The latter study reported a 517C3 T transition on 5 of 1,586 chromosomes in the Swedish population (allelic frequency 0.3%), leading to a substitution of arginine (R) 173 for cysteine (C) in a putative nuclear localization sequence (NLS) of BACH1. 10 NLS is a short peptide sequence necessary and sufficient for nuclear localization of a protein, 11 and single amino acid substitution involving critical residues in NLS has been shown to impair the nuclear localization. 12 Deletion of arginine or lysine in the NLS of BLM resulted in an even ...

Tagging Single Nucleotide Polymorphisms in the BRIP1 Gene and Susceptibility to Breast and Ovarian Cancer

“…Another study has indicated that the rare variant Arg173Cys (tSNP rs4988345) impairs protein translocation to the nucleus and might modify breast cancer susceptibility [17], [26]. Since the minor allele for this variant is very rare (MAF = 0.008) in CEPH samples, we have very limited power to confirm or refute this association using the case-control population in the current study.…”

Further evidence for the contribution of the BRCA1-interacting protein-terminal helicase 1 (BRIP1) gene in breast cancer susceptibility

“…Previous studies have indicated that the rare BRIP1 variant rs4988345 (Arg173Cys) impairs protein translocation to the nucleus and may also modify breast cancer susceptibility (Lei and Vorechovsky, 2003;Song et al, 2007). Since the MAF for this variant is very low (0.0065) in the Chinese Han population, we had limited power to confirm or refute this association using the case-control population of the current study.…”

“…Previous studies have analyzed potential associations between BRIP1 variants and breast cancer risk, either by mutation analysis or by genotyping, to select single nucleotide polymorphisms (SNPs) within the gene (Lei and Vorechovsky, 2003;Rutter et al, 2003;Sigurdson et al, 2004;Lewis et al, 2005;Garcia-Closas et al, 2006;Vahteristo et al, 2006). Although the rs2048718 (5ꞌ-untranslated region, UTR), rs4988345 (exon 15), and rs4986764 (exon 18) polymorphisms have been previously examined in the context of breast cancer, these genetic association studies have failed to produce consistent results (Luo et al, 2002;Lei and Vorechovsky, 2003;Song et al, 2007;Pabalan et al, 2013). Furthermore, several important SNPs, such as rs2048718, rs4986764, rs4986763, rs11079454, and rs7213430, have not been included in previous studies.…”

Mutational analysis of the breast cancer susceptibility gene BRIP1 /BACH1/FANCJ in high-risk non-BRCA1/BRCA2 breast cancer families

“…In addition, phosphorylation of the Ser990 residue triggers FANCJ interaction with BRCT domains of BRCA1, which is required for establishment of the G2 cell-cycle checkpoint response to DNA damage (Yu et al 2003). Proper localization of FANCJ to the nucleus is impaired by the c.517C [ T variant (p.Arg173Cys) (Lei et al 2003), which has been suggested to have an effect on breast cancer susceptibility. Furthermore, enzymatic activity of FANCJ was found defective in two patients with germline FANCJ coding sequence mutations who experienced early onset breast cancer (Cantor et al 2004).…”