BRCA1/2 mutations perturb telomere biology: characterization of structural and functional abnormalities in vitro and in vivo

BRCA1 mutation is associated with carcinogenesis, especially of breast tissue. Telomere maintenance is crucial for malignant transformation. Being a part of the DNA repair machinery, BRCA1 may be implicated in telomere biology. We explored the role of BRCA1 in telomere maintenance in lymphocytes of BRCA1/2 mutation carriers and in in vitro system by knocking down its expression in non-malignant breast epithelial cells. The results in both systems were similar. BRCA1/2 mutation caused perturbation of telomere homeostasis, shortening of the single stranded telomere overhang and increased the intercellular telomere length variability as well as the number of telomere free chromosomal ends and telomeric circles. These changes resulted in an increased DNA damage status. Telomerase activity, inducibility and expression remained unchanged. BRCA1 mutation resulted also in changes in the binding of shelterin proteins to telomeres. DNMT-1 levels were markedly reduced both in the carriers and in in vitro system. The methylation pattern of the sub-telomeric regions in carriers suggested hypomethylation in chromosome 10. The expression of a distinct set of genes was also changed, some of which may relate to pre-disposition to malignancy. These results show that BRCA gene products have a role in telomere length homeostasis. It is plausible that these perturbations contribute to malignant transformation in BRCA mutants.

[1]  A. Teschendorff,et al.  A BRCA1-mutation associated DNA methylation signature in blood cells predicts sporadic breast cancer incidence and survival , 2014, Genome Medicine.

[2]  N. Chandel.  Mitochondria and cancer , 2014, Cancer & metabolism.

[3]  S. Tsugane,et al.  Global methylation levels in peripheral blood leukocyte DNA by LUMA and breast cancer: a case–control study in Japanese women , 2014, British Journal of Cancer.

[4]  R. Eeles,et al.  Lymphocyte Telomere Length Is Long in BRCA1 and BRCA2 Mutation Carriers Regardless of Cancer-Affected Status , 2014, Cancer Epidemiology, Biomarkers & Prevention.

[5]  Chen Cao,et al.  Regulation of DNA methyltransferase 1 transcription in BRCA1-mutated breast cancer: a novel crosstalk between E2F1 motif hypermethylation and loss of histone H3 lysine 9 acetylation , 2014, Molecular Cancer.

[6]  R. Eeles,et al.  Telomere Length Shows No Association with BRCA1 and BRCA2 Mutation Status , 2014, PloS one.

[7]  L. Gollahon,et al.  Mitotic perturbations induced by Nek2 overexpression require interaction with TRF1 in breast cancer cells , 2013, Cell cycle.

[8]  J. Benítez,et al.  Short telomeres are frequent in hereditary breast tumors and are associated with high tumor grade , 2013, Breast Cancer Research and Treatment.

[9]  Diana Eccles,et al.  Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. , 2013, Journal of the National Cancer Institute.

[10]  E. Rosen.  BRCA1 in the DNA damage response and at telomeres , 2013, Front. Genet..

[11]  J. Viñas-Salas,et al.  Telomeric repeat factor 1 protein levels correlates with telomere length in colorectal cancer. , 2012, Revista espanola de enfermedades digestivas : organo oficial de la Sociedad Espanola de Patologia Digestiva.

[12]  B. Tu,et al.  Mitochondrial localization of telomeric protein TIN2 links telomere regulation to metabolic control. , 2012, Molecular cell.

[13]  T. Irimura,et al.  Mucin 21 in esophageal squamous epithelia and carcinomas: analysis with glycoform-specific monoclonal antibodies. , 2012, Glycobiology.

[14]  Kimberly S. Butler,et al.  Coordinate regulation between expression levels of telomere-binding proteins and telomere length in breast carcinomas , 2012, Cancer medicine.

[15]  Jianing Xu,et al.  Maintenance of Very Long Telomeres by Recombination in the Kluyveromyces lactis stn1-M1 Mutant Involves Extreme Telomeric Turnover, Telomeric Circles, and Concerted Telomeric Amplification , 2012, Molecular and Cellular Biology.

[16]  Ahmedin Jemal,et al.  Breast cancer statistics, 2011 , 2011, CA: a cancer journal for clinicians.

[17]  M. Urioste,et al.  Genetic Anticipation Is Associated with Telomere Shortening in Hereditary Breast Cancer , 2011, PLoS genetics.

[18]  Raffaella Diotti,et al.  Shelterin complex and associated factors at human telomeres , 2011, Nucleus.

[19]  X. Coumoul,et al.  BRCA1 affects global DNA methylation through regulation of DNMT1 , 2010, Cell Research.

[20]  P. Santulli,et al.  Research resource: genome-wide profiling of methylated promoters in endometriosis reveals a subtelomeric location of hypermethylation. , 2010, Molecular endocrinology.

[21]  J. Oosterwijk,et al.  Penetrance of breast cancer, ovarian cancer and contralateral breast cancer in BRCA1 and BRCA2 families: high cancer incidence at older age , 2010, Breast Cancer Research and Treatment.

[22]  Yang Zhang,et al.  Expression of TRF1, TRF2, TIN2, TERT, KU70, and BRCA1 proteins is associated with telomere shortening and may contribute to multistage carcinogenesis of gastric cancer , 2010, Journal of Cancer Research and Clinical Oncology.

[23]  Karthik Devarajan,et al.  Altered Gene Expression in Morphologically Normal Epithelial Cells from Heterozygous Carriers of BRCA1 or BRCA2 Mutations , 2010, Cancer Prevention Research.

[24]  J. Solinger,et al.  The Caenorhabditis elegans Elongator Complex Regulates Neuronal α-tubulin Acetylation , 2010, PLoS genetics.

[25]  Amy Y. M. Au,et al.  DNA C-circles are specific and quantifiable markers of alternative-lengthening-of-telomeres activity , 2009, Nature Biotechnology.

[26]  E. Rosen,et al.  BRCA1 Localization to the Telomere and Its Loss from the Telomere in Response to DNA Damage* , 2009, The Journal of Biological Chemistry.

[27]  Jing Chen,et al.  ToppGene Suite for gene list enrichment analysis and candidate gene prioritization , 2009, Nucleic Acids Res..

[28]  E. Cabuy,et al.  BRCA1 knock-down causes telomere dysfunction in mammary epithelial cells , 2009, Cytogenetic and Genome Research.

[29]  M. Malumbres,et al.  TRF1 Controls Telomere Length and Mitotic Fidelity in Epithelial Homeostasis , 2009, Molecular and Cellular Biology.

[30]  Wilhelm Palm,et al.  How shelterin protects mammalian telomeres. , 2008, Annual review of genetics.

[31]  K. Miyazono,et al.  Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway , 2008, Oncogene.

[32]  Ron Shamir,et al.  SPIKE – a database, visualization and analysis tool of cellular signaling pathways , 2008, BMC Bioinformatics.

[33]  L. Comai,et al.  WRN Controls Formation of Extrachromosomal Telomeric Circles and Is Required for TRF2ΔB-Mediated Telomere Shortening , 2008, Molecular and Cellular Biology.

[34]  George Tseng,et al.  Glutathione peroxidase 3, deleted or methylated in prostate cancer, suppresses prostate cancer growth and metastasis. , 2007, Cancer research.

[35]  M. Blasco,et al.  Telomere length regulates the epigenetic status of mammalian telomeres and subtelomeres , 2007, Nature Genetics.

[36]  A. D’Andrea,et al.  Molecular pathogenesis of Fanconi anemia: recent progress. , 2006, Blood.

[37]  Xuehao Wang,et al.  Tumorigenic study on hepatocytes coexpressing SV40 with Ras , 2006, Molecular carcinogenesis.

[38]  M. Fraga,et al.  DNA methyltransferases control telomere length and telomere recombination in mammalian cells , 2006, Nature Cell Biology.

[39]  Jasmyn A. Dunn,et al.  Disruption of BRCA1 function results in telomere lengthening and increased anaphase bridge formation in immortalized cell lines , 2006, Genes, chromosomes & cancer.

[40]  P. ten Dijke,et al.  The tumor suppressor Smad4 is required for transforming growth factor beta-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells. , 2006, Cancer research.

[41]  T. Ide,et al.  G-tail telomere HPA: simple measurement of human single-stranded telomeric overhangs , 2005, Nature Methods.

[42]  W. El-Deiry,et al.  Cooperation between BRCA1 and p53 in repair of cyclobutane pyrimidine dimers , 2005, Cancer biology & therapy.

[43]  T. Lange,et al.  Shelterin: the protein complex that shapes and safeguards human telomeres , 2005 .

[44]  C. Heldin,et al.  TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. , 2005, Molecular biology of the cell.

[45]  N. Pavletich,et al.  The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA–ssDNA junction , 2005, Nature.

[46]  T. Lange,et al.  Homologous Recombination Generates T-Loop-Sized Deletions at Human Telomeres , 2004, Cell.

[47]  J. Londoño-Vallejo.  Telomere length heterogeneity and chromosome instability. , 2004, Cancer letters.

[48]  M. Blasco.  Carcinogenesis Young Investigator Award. Telomere epigenetics: a higher-order control of telomere length in mammalian cells. , 2004, Carcinogenesis.

[49]  Simon C Watkins,et al.  Resolution of anaphase bridges in cancer cells , 2004, Chromosoma.

[50]  J. Shay,et al.  Modification of Subtelomeric DNA , 2004, Molecular and Cellular Biology.

[51]  E. Rosen,et al.  BRCA1 Inhibition of Telomerase Activity in Cultured Cells , 2003, Molecular and Cellular Biology.

[52]  M. Mceachern,et al.  Factors Influencing the Recombinational Expansion and Spread of Telomeric Tandem Arrays in Kluyveromyces lactis , 2003, Eukaryotic Cell.

[53]  J. Hopper,et al.  Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. , 2003, American journal of human genetics.

[54]  Rafael A Irizarry,et al.  Exploration, normalization, and summaries of high density oligonucleotide array probe level data. , 2003, Biostatistics.

[55]  W. Hahn,et al.  Erosion of the telomeric single-strand overhang at replicative senescence , 2003, Nature Genetics.

[56]  Derek Davies,et al.  BRCA2-dependent and independent formation of RAD51 nuclear foci , 2003, Oncogene.

[57]  S. West.  Cross-links between Fanconi anaemia and BRCA2. , 2003, DNA Repair.

[58]  Hans Joenje,et al.  Biallelic Inactivation of BRCA2 in Fanconi Anemia , 2002, Science.

[59]  P. Lansdorp,et al.  Quantitative Fluorescence In Situ Hybridization (Q‐FISH) , 2001, Current protocols in cell biology.

[60]  G. Iliakis,et al.  Deficiency of human BRCA2 leads to impaired homologous recombination but maintains normal nonhomologous end joining , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[61]  J. Shay,et al.  Telomerase and cancer. , 2001, Human molecular genetics.

[62]  A. Bird,et al.  Densely methylated sequences that are preferentially localized at telomere-proximal regions of human chromosomes. , 1999, Gene.

[63]  J. Campisi,et al.  TIN2, a new regulator of telomere length in human cells , 1999, Nature Genetics.

[64]  G E Tomlinson,et al.  BRCA2 is required for ionizing radiation-induced assembly of Rad51 complex in vivo. , 1999, Cancer research.

[65]  Y. Lau,et al.  Effect of insulin‐like growth factor 1 on PHA‐stimulated cord blood mononuclear cell telomerase activity , 1999, British journal of haematology.

[66]  A. Kowald,et al.  Possible mechanisms for the regulation of telomere length. , 1997, Journal of molecular biology.

[67]  C. Harris,et al.  Genomic instability and telomerase activity in human bronchial epithelial cells during immortalization by human papillomavirus-16 E6 and E7 genes. , 1997, Experimental cell research.

[68]  A. Sartorelli,et al.  Differentiation of immortal cells inhibits telomerase activity. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[69]  C. Harley,et al.  Stabilization of short telomeres and telomerase activity accompany immortalization of Epstein-Barr virus-transformed human B lymphocytes , 1994, Journal of virology.

[70]  J. Steitz,et al.  Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. , 1992, The EMBO journal.

[71]  R. Myers,et al.  Structure and variability of human chromosome ends , 1990, Molecular and cellular biology.

[72]  Carol W. Greider,et al.  Identification of a specific telomere terminal transferase activity in tetrahymena extracts , 1985, Cell.

[73]  Wen-bing Yang 杨文兵,et al.  Correlations of MUC15 overexpression with clinicopathological features and prognosis of glioma , 2014, Journal of Huazhong University of Science and Technology [Medical Sciences].

[74]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[75]  E. Blackburn,et al.  Recognition and elongation of telomeres by telomerase. , 1989, Genome.