Potential G-quadruplex formation at breakpoint regions of chromosomal translocations in cancer may explain their fragility.

Genetic alterations like point mutations, insertions, deletions, inversions and translocations are frequently found in cancers. Chromosomal translocations are one of the most common genomic aberrations associated with nearly all types of cancers especially leukemia and lymphoma. Recent studies have shown the role of non-B DNA structures in generation of translocations. In the present study, using various bioinformatic tools, we show the propensity of formation of different types of altered DNA structures near translocation breakpoint regions. In particular, we find close association between occurrence of G-quadruplex forming motifs and fragile regions in almost 70% of genes involved in rearrangements in lymphoid cancers. However, such an analysis did not provide any evidence for the occurrence of G-quadruplexes at the close vicinity of translocation breakpoint regions in nonlymphoid cancers. Overall, this study will help in the identification of novel non-B DNA targets that may be responsible for generation of chromosomal translocations in cancer.

[1]  M. Nussenzweig,et al.  A role for AID in chromosome translocations between c-myc and the IgH variable region , 2007, Journal of Experimental Medicine.

[2]  Thomas Ried,et al.  AID produces DNA double-strand breaks in non-Ig genes and mature B cell lymphomas with reciprocal chromosome translocations. , 2009, Molecular cell.

[3]  M. Nussenzweig,et al.  AID Is Required for the Chromosomal Breaks in c-myc that Lead to c-myc/IgH Translocations , 2008, Cell.

[4]  N. Maizels,et al.  AID binds to transcription-induced structures in c-MYC that map to regions associated with translocation and hypermutation , 2005, Oncogene.

[5]  J. Rowley,et al.  Chromosome translocations: dangerous liaisons revisited , 2001, Nature Reviews Cancer.

[6]  Shankar Balasubramanian,et al.  Prevalence of quadruplexes in the human genome , 2005, Nucleic acids research.

[7]  S. Lewis,et al.  Cryptic signals and the fidelity of V(D)J joining , 1997, Molecular and cellular biology.

[8]  A. Chinnaiyan,et al.  Recurrent gene fusions in prostate cancer , 2008, Nature Reviews Cancer.

[9]  F. J. Novo,et al.  TICdb: a collection of gene-mapped translocation breakpoints in cancer , 2007, BMC Genomics.

[10]  S. Neidle,et al.  Highly prevalent putative quadruplex sequence motifs in human DNA , 2005, Nucleic acids research.

[11]  S. Raghavan,et al.  Chromosomal translocations in cancer. , 2008, Biochimica et biophysica acta.

[12]  M. Lieber,et al.  Analysis of the V(D)J Recombination Efficiency at Lymphoid Chromosomal Translocation Breakpoints* , 2001, The Journal of Biological Chemistry.

[13]  R. Sinden DNA Structure and Function , 1994 .

[14]  B. Emanuel,et al.  Cruciform DNA Structure Underlies the Etiology for Palindrome-mediated Human Chromosomal Translocations* , 2004, Journal of Biological Chemistry.

[15]  M. Nussenzweig,et al.  Origin of Chromosomal Translocations in Lymphoid Cancer , 2010, Cell.

[16]  M. Lieber,et al.  DNA structures at chromosomal translocation sites. , 2006, BioEssays : news and reviews in molecular, cellular and developmental biology.

[17]  P. Swanson,et al.  V(D)J Recombinase Binding and Cleavage of Cryptic Recombination Signal Sequences Identified from Lymphoid Malignancies* , 2008, Journal of Biological Chemistry.

[18]  B. Emanuel,et al.  Palindrome-mediated chromosomal translocations in humans. , 2006, DNA repair.

[19]  Tactggtat Agcctagatgtgtttaga,et al.  J-mediated Translocations in Lymphoid Neoplasms : A Functional Assessment of Genomic Instability by Cryptic Sites , 2001 .

[20]  J. Sklar,et al.  Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint-cluster region near a transcriptionally active locus on chromosome 18. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Steven J. M. Jones,et al.  Circos: an information aesthetic for comparative genomics. , 2009, Genome research.

[22]  S. Raghavan,et al.  Mechanism of Fragility at BCL2 Gene Minor Breakpoint Cluster Region during t(14;18) Chromosomal Translocation* , 2012, The Journal of Biological Chemistry.

[23]  R. Wells,et al.  Non-B DNA Conformations, Genomic Rearrangements, and Human Disease* , 2004, Journal of Biological Chemistry.

[24]  S. Korsmeyer,et al.  Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around Jh on chromosome 14 and near a transcriptional unit on 18 , 1985, Cell.

[25]  M. Lieber,et al.  A non-B-DNA structure at the Bcl-2 major breakpoint region is cleaved by the RAG complex , 2004, Nature.

[26]  Shantanu Chowdhury,et al.  QuadBase: genome-wide database of G4 DNA—occurrence and conservation in human, chimpanzee, mouse and rat promoters and 146 microbes , 2007, Nucleic Acids Res..

[27]  S. Raghavan,et al.  How does DNA break during chromosomal translocations? , 2011, Nucleic acids research.

[28]  B. Roe,et al.  Regions of genomic instability on 22q11 and 11q23 as the etiology for the recurrent constitutional t(11;22). , 2000, Human molecular genetics.

[29]  S. Korsmeyer,et al.  Mechanism of the t(14;18) chromosomal translocation: structural analysis of both derivative 14 and 18 reciprocal partners. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[30]  S. Korsmeyer,et al.  Chromosomal translocations in lymphoid malignancies reveal novel proto-oncogenes. , 1992, Annual review of immunology.

[31]  Mingming Jia,et al.  COSMIC (the Catalogue of Somatic Mutations in Cancer): a resource to investigate acquired mutations in human cancer , 2009, Nucleic Acids Res..

[32]  Yunmei Ma,et al.  Double-Strand Break Formation by the RAG Complex at the Bcl-2 Major Breakpoint Region and at Other Non-B DNA Structures In Vitro , 2005, Molecular and Cellular Biology.

[33]  M. Nussenzweig,et al.  AID Is Required for c-myc/IgH Chromosome Translocations In Vivo , 2004, Cell.

[34]  Ming Yi,et al.  Non-B DB: a database of predicted non-B DNA-forming motifs in mammalian genomes , 2010, Nucleic Acids Res..

[35]  T. Rabbitts,et al.  Chromosomal translocations in human cancer , 1994, Nature.

[36]  Stephen Neidle,et al.  Quadruplex nucleic acids. , 2006 .

[37]  David N Cooper,et al.  Breakpoints of gross deletions coincide with non-B DNA conformations. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[38]  D. Schatz,et al.  The RAG proteins and V(D)J recombination: complexes, ends, and transposition. , 2000, Annual review of immunology.

[39]  R. Sinden Biological implications of the DNA structures associated with disease-causing triplet repeats. , 1999, American journal of human genetics.

[40]  Mingming Jia,et al.  COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer , 2010, Nucleic Acids Res..

[41]  J. Rowley A New Consistent Chromosomal Abnormality in Chronic Myelogenous Leukaemia identified by Quinacrine Fluorescence and Giemsa Staining , 1973, Nature.

[42]  J. Tchinda,et al.  Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. , 2006, Science.

[43]  P. Nowell,et al.  A minute chromosome in human chronic granulocytic leukemia , 1960 .

[44]  S. Dhanasekaran,et al.  Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer , 2007, Nature.

[45]  M. Lieber,et al.  Formation of a G-quadruplex at the BCL2 major breakpoint region of the t(14;18) translocation in follicular lymphoma , 2010, Nucleic acids research.