Pericentromeric instability and spontaneous emergence of human neoacrocentric and minute chromosomes in the alternative pathway of telomere lengthening.

In the alternative pathway of telomere lengthening (ALT), neoplastic cell growth is prolonged by telomere recombination. We show that ALT is unexpectedly characterized by high rates of ongoing pericentromeric chromosomal instability. Combined with telomeric recombination, ALT pericentromeric instability generates neoacrocentric chromosomes. In the present studies, we describe a subgroup of ALT neoacrocentric minute chromosomes, composed of DNA entities two to five times smaller in size than human chromosome 21. The frequencies of ALT minute chromosomes were increased by gamma-irradiation and suppressed by telomerase. Continuous growth after telomerase inhibition/depletion was followed by increased rates of telomeric sister chromatid recombination and the emergence of minute chromosomes. We show that ALT minute chromosomes were derived from true centromeric fissions and/or chromosomal breakage/fusion/bridge cycles. They exhibit a two-chromatid structure, carry genomic DNA, centromeric and telomeric repeats, and display regular mitotic functionality. These observations are important in understanding the global genomic instability that characterizes most human advanced malignancies.

[1]  R. Reddel,et al.  Disruption of Telomere Maintenance by Depletion of the MRE11/RAD50/NBS1 Complex in Cells That Use Alternative Lengthening of Telomeres* , 2007, Journal of Biological Chemistry.

[2]  R. Reddel,et al.  DNA damage induces alternative lengthening of telomeres (ALT) associated promyelocytic leukemia bodies that preferentially associate with linear telomeric DNA. , 2007, Cancer research.

[3]  Wendy S. Wright,et al.  (www.interscience.wiley.com) DOI: 10.1002/path.2090 Review Article Hallmarks of telomeres in ageing research , 2022 .

[4]  Andreas Prlic,et al.  Ensembl 2007 , 2006, Nucleic Acids Res..

[5]  R. Bristow,et al.  Promyelocytic leukemia nuclear bodies behave as DNA damage sensors whose response to DNA double-strand breaks is regulated by NBS1 and the kinases ATM, Chk2, and ATR , 2006, The Journal of cell biology.

[6]  J. Squire,et al.  The breakage–fusion–bridge (BFB) cycle as a mechanism for generating genetic heterogeneity in osteosarcoma , 2006, Chromosoma.

[7]  R. Reddel,et al.  The first molecular details of ALT in human tumor cells. , 2005, Human molecular genetics.

[8]  Susan M. Butler,et al.  Going against the grain: chemotaxis and infection in Vibrio cholerae , 2005, Nature Reviews Microbiology.

[9]  M. Blasco.  Telomeres and human disease: ageing, cancer and beyond , 2005, Nature Reviews Genetics.

[10]  M. Gatti,et al.  The mechanism of telomere protection: a comparison between Drosophila and humans , 2005, Chromosoma.

[11]  S. Gagos,et al.  Chromosome instability in neoplasia: chaotic roots to continuous growth. , 2005, The international journal of biochemistry & cell biology.

[12]  Joydeep Basu,et al.  Artificial and engineered chromosomes: non-integrating vectors for gene therapy. , 2005, Trends in molecular medicine.

[13]  J. Murnane,et al.  The Loss of a Single Telomere Can Result in Instability of Multiple Chromosomes in a Human Tumor Cell Line , 2005, Molecular Cancer Research.

[14]  M. Blasco,et al.  The telomerase RNA component Terc is required for the tumour‐promoting effects of Tert overexpression , 2005, EMBO reports.

[15]  P. Sham,et al.  TTF-1 and RET promoter SNPs: regulation of RET transcription in Hirschsprung's disease. , 2005, Human molecular genetics.

[16]  J. Shay,et al.  Telomeric Recombination in Mismatch Repair Deficient Human Colon Cancer Cells after Telomerase Inhibition , 2004, Cancer Research.

[17]  S. West,et al.  Telomere Maintenance Requires the RAD51D Recombination/Repair Protein , 2004, Cell.

[18]  Carlo Rago,et al.  Inactivation of hCDC4 can cause chromosomal instability , 2004, Nature.

[19]  F. Pellestor,et al.  Primed in situ (PRINS) Labelling with Alu and Satellite Primers for Rapid Characterization of Human Chromosomes in Hybrid Cell Lines , 1997, Chromosome Research.

[20]  T. Jenuwein,et al.  Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases , 2004, Nature Genetics.

[21]  M. Brenneman,et al.  Frequent recombination in telomeric DNA may extend the proliferative life of telomerase-negative cells. , 2004, Nucleic acids research.

[22]  M. Mann,et al.  ERCC1/XPF removes the 3' overhang from uncapped telomeres and represses formation of telomeric DNA-containing double minute chromosomes. , 2003, Molecular cell.

[23]  P. Sorensen,et al.  Spectral karyotyping identifies recurrent complex rearrangements of chromosomes 8, 17, and 20 in osteosarcomas , 2003, Genes, chromosomes & cancer.

[24]  R. DePinho,et al.  Telomere-based crisis: functional differences between telomerase activation and ALT in tumor progression. , 2003, Genes & development.

[25]  Dimitris Thanos,et al.  Integration of Long-Term-Memory-Related Synaptic Plasticity Involves Bidirectional Regulation of Gene Expression and Chromatin Structure , 2002, Cell.

[26]  S. Jackson,et al.  Sensing and repairing DNA double-strand breaks. , 2002, Carcinogenesis.

[27]  J. Hackett,et al.  Balancing instability: dual roles for telomerase and telomere dysfunction in tumorigenesis , 2002, Oncogene.

[28]  S M Bailey,et al.  Strand-Specific Postreplicative Processing of Mammalian Telomeres , 2001, Science.

[29]  J. Shay,et al.  Telomerase Can Inhibit the Recombination-based Pathway of Telomere Maintenance in Human Cells* , 2001, The Journal of Biological Chemistry.

[30]  M. Bibikova,et al.  Mre11 protein complex prevents double-strand break accumulation during chromosomal DNA replication. , 2001, Molecular cell.

[31]  A. Jauch,et al.  Alternative lengthening of telomeres is associated with chromosomal instability in osteosarcomas , 2001, Oncogene.

[32]  V. Lundblad,et al.  Defects in mismatch repair promote telomerase-independent proliferation , 2001, Nature.

[33]  H. Masumoto,et al.  Human CENP-H multimers colocalize with CENP-A and CENP-C at active centromere--kinetochore complexes. , 2000, Human molecular genetics.

[34]  D. Gisselsson,et al.  Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Y. Pommier,et al.  Initiation of DNA Fragmentation during Apoptosis Induces Phosphorylation of H2AX Histone at Serine 139* , 2000, The Journal of Biological Chemistry.

[36]  S. Teng,et al.  Telomere-Telomere Recombination Is an Efficient Bypass Pathway for Telomere Maintenance in Saccharomyces cerevisiae , 1999, Molecular and Cellular Biology.

[37]  D. Gisselsson,et al.  Variable stability of chromosomes containing amplified α-satellite sequences in human mesenchymal tumours , 1999, Chromosoma.

[38]  R. Reddel,et al.  Telomerase-negative immortalized human cells contain a novel type of promyelocytic leukemia (PML) body. , 1999, Cancer research.

[39]  R. Reddel,et al.  Telomere elongation in immortal human cells without detectable telomerase activity. , 1995, The EMBO journal.

[40]  C B Harley,et al.  Specific association of human telomerase activity with immortal cells and cancer. , 1994, Science.

[41]  R. Moyzis,et al.  Apparent lack of telomere sequences on double minute chromosomes. , 1990, Cancer genetics and cytogenetics.

[42]  Iscn.  International System for Human Cytogenetic Nomenclature , 1978 .