Mechanisms of Chromosome Translocations in Cancer


Chromosome translocations have long been known to be causative events in cancer. First observed as recurrent translocations in lymphomas and leukaemias, translocations are also found in solid tumours. One of the key hallmarks of cancer is genome instability, and chromosome translocations represent a critical form of genome instability that reflects mis‐repair of DNA double‐strand breaks (DSBs). DSBs are repaired by two main pathways, non‐homologous end joining and homologous recombination, and chromosome translocations can be created by both of these pathways. Many translocations associated with specific cancers are recurrent, reflecting selective pressure for inactivated tumour suppressor genes or activated oncogenes, which are early drivers of cancer phenotypes. Cancer therapeutics, including DNA reactive chemicals, topoisomerase inhibitors and radiation, are effective cancer treatments, but they can induce translocation‐mediated secondary malignancies at significant frequencies. Reducing the risk of these sequelae is an important goal in cancer research.

Key Concepts

  • Chromosome translocations are critical genomic rearrangements that are frequently found in lymphoid and solid tumours and other diseases.
  • Translocations arise when DNA double‐strand breaks arise simultaneously on two separate chromosomes and are mis‐rejoined.
  • Translocations observed in cancer may inactivate tumour suppressor genes or activate oncogenes by gene fusion or juxtaposition of a strong promoter with a proto‐oncogene.
  • Translocations are formed primarily through alternative non‐homologous end joining, but other double‐strand break repair mechanisms can contribute to translocation spectra, including classical non‐homologous end joining, homologous recombination and single‐strand annealing.
  • Cancer therapeutics may cause translocations that generate secondary, therapy‐induced cancers.
  • Translocation efficiency and junction positions are regulated by many factors including programmed DNA double‐strand breaks, spontaneous and induced DNA damage, DNA repair pathways, structural elements in DNA sequences such as repeated sequences and palindromes, relative locations chromosomes within nuclei and epigenetic factors.

Keywords: genome instability; DNA repair; chromatin; cancer therapy; oncogenes; tumour suppressor genes; epigenetics; non‐homologous end joining; homologous recombination

Figure 1. Types and consequences of chromosome translocations. (a) Balanced translocations result from reciprocal exchange in which little or no sequence information is lost. Depending on the position of the exchange (X), chromosome translocations can produce stable mono‐centric chromosomes (left) or unstable dicentric and acentric chromosomes (right). (b) Unbalanced translocations result from nonreciprocal exchange in which a segment from one chromosome is lost. (c) Translocations can activate proto‐oncogenes by juxtaposing a strong promoter and a proto‐oncogene, causing overexpression. (d) Translocation breakpoints within genes can cause gene inactivation, that is, of a tumour suppressor. (e) Translocations can fuse two genes (or specific exons, e.g. Ex1, Ex2) to create novel oncogenes. In this illustration the exchange occurs within introns.
Figure 2. DSB repair by NHEJ and HR. (a) NHEJ comprises two subpathways, cNHEJ and aNHEJ. Both initiate with DSB recognition and limited end‐processing by the MRN complex. 53BP1, RIF1 and Ku suppress end resection. Ku binds DNA ends and recruits DNA‐PKcs, which aligns ends for repair by Ligase IV and its accessory factors XRCC4 and XLF. aNHEJ requires limited resection by MRN and CtIP to expose microhomologies, which align ends, forming flaps that are trimmed, and repair is completed by Ligase III and XRCC1. (b) HR initiates with limited resection by MRN and CtIP, and more extensive resection is catalysed by Exo1 or Dna2. RPA binds single‐stranded DNA and is exchanged for RAD51 by many mediator proteins (not shown). The RAD51 nucleoprotein filament invades a homologous sequence and the 3′ end is extended by DNA polymerase δ. The extended strand can be released to anneal with the resected strand on the opposite side of the DSB (SDSA; no crossover), or the second end can invade, forming a double Holliday junction that can be resolved with or without a crossover; the crossover pathway can produce a translocation if HR occurs between homologous sequences on different chromosomes.
Figure 3. DSB repair by single‐strand annealing. (a) SSA involves extensive resection as with HR (Figure b). When a DSB occurs within or between direct repeats, resection can expose complementary strands in each repeat that anneal to form a deletion product. (b) SSA between repeats on separate chromosomes can produce translocations.


Allen C, Ashley AK, Hromas R, et al. (2011) More forks on the road to replication stress recovery. Journal of Molecular Cell Biology 3: 4–12.

Bunting SF and Nussenzweig A (2013) End‐joining, translocations and cancer. Nature Reviews Cancer 13: 443–454.

Ciccia A and Elledge SJ (2010) The DNA damage response: making it safe to play with knives. Molecular Cell 40: 179–204.

Cook PR (2010) A model for all genomes: the role of transcription factories. Journal of Molecular Biology 395: 1–10.

Daniel JA and Nussenzweig A (2013) The AID‐induced DNA damage response in chromatin. Molecular Cell 50: 309–321.

Debatisse M, Le Tallec B, Letessier A, et al. (2012) Common fragile sites: mechanisms of instability revisited. Trends in Genetics 28: 22–32.

DesJarlais R and Tummino PJ (2016) Role of histone‐modifying enzymes and their complexes in regulation of chromatin biology. Biochemistry 55: 1584–1599.

Elliott B, Richardson C and Jasin M (2005) Chromosomal translocation mechanisms at intronic alu elements in mammalian cells. Molecular Cell 17: 885–894.

Felix CA, Kolaris CP and Osheroff N (2006) Topoisomerase II and the etiology of chromosomal translocations. DNA Repair 5: 1093–1108.

Fenech M, Kirsch‐Volders M, Natarajan AT, et al. (2011) Molecular mechanisms of micronucleus, nucleoplasmic bridge and nuclear bud formation in mammalian and human cells. Mutagenesis 26: 125–132.

Hanahan D and Weinberg RA (2000) The hallmarks of cancer. Cell 100: 57–70.

Hanahan D and Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144: 646–674.

Hanks S, Coleman K, Reid S, et al. (2004) Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nature Genetics 36: 1159–1161.

Huang F, Goyal N, Sullivan K, et al. (2016) Targeting BRCA1‐ and BRCA2‐deficient cells with RAD52 small molecule inhibitors. Nucleic Acids Research 44: 4189–4199.

Hwang JK, Alt FW and Yeap LS (2015) Related mechanisms of antibody somatic hypermutation and class switch recombination. Microbiology Spectrum 3: 1–22.

Jackson SP (2002) Sensing and repairing DNA double‐strand breaks. Carcinogenesis 23: 687–696.

Kurahashi H, Inagaki H, Ohye T, et al. (2006) Palindrome‐mediated chromosomal translocations in humans. DNA Repair 5: 1136–1145.

Lieber MR (2010) The mechanism of double‐strand DNA break repair by the nonhomologous DNA end‐joining pathway. Annual Review of Biochemistry 79: 181–211.

Mani RS and Chinnaiyan AM (2010) Triggers for genomic rearrangements: insights into genomic, cellular and environmental influences. Nature Reviews Genetics 11: 819–829.

Mazouzi A, Velimezi G and Loizou JI (2014) DNA replication stress: causes, resolution and disease. Experimental Cell Research 329: 85–93.

Mladenov E, Magin S, Soni A, et al. (2016) DNA double‐strand‐break repair in higher eukaryotes and its role in genomic instability and cancer: cell cycle and proliferation‐dependent regulation. Seminars in Cancer Biology 37–38: 51–64.

Murnane JP (2012) Telomere dysfunction and chromosome instability. Mutation Research 730: 28–36.

Nambiar M, Kari V and Raghavan SC (2008) Chromosomal translocations in cancer. Biochimica et Biophysica Acta 1786: 139–152.

Nambiar M and Raghavan SC (2011) How does DNA break during chromosomal translocations? Nucleic Acids Research 39: 5813–5825.

Osley MA, Tsukuda T and Nickoloff JA (2007) ATP‐dependent chromatin remodeling factors and DNA damage repair. Mutation Research 618: 65–80.

Pendleton M, Lindsey RH Jr, Felix CA, et al. (2014) Topoisomerase II and leukemia. Annals of the New York Academy of Sciences 1310: 98–110.

Pommier Y, Leo E, Zhang H, et al. (2010) DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chemistry & Biology 17: 421–433.

Richardson C and Jasin M (2000) Frequent chromosomal translocations induced by DNA double‐strand breaks. Nature 405: 697–700.

Roth DB (2014) V(D)J recombination: mechanism, errors, and fidelity. Microbiology Spectrum 2: 1–11.

Roukos V, Burman B and Misteli T (2013) The cellular etiology of chromosome translocations. Current Opinion in Cell Biology 25: 357–364.

Roukos V and Misteli T (2014) The biogenesis of chromosome translocations. Nature Cell Biology 16: 293–300.

Sexton T and Cavalli G (2015) The role of chromosome domains in shaping the functional genome. Cell 160: 1049–1059.

Sfeir A and Symington LS (2015) Microhomology‐mediated end joining: a back‐up survival mechanism or dedicated pathway? Trends in Biochemical Sciences 40: 701–714.

Simsek D, Brunet E, Wong SY, et al. (2011) DNA ligase III promotes alternative nonhomologous end‐joining during chromosomal translocation formation. PLoS Genetics 7: e1002080.

Smeenk G and van Attikum H (2013) The chromatin response to DNA breaks: leaving a mark on genome integrity. Annual Review of Biochemistry 82: 55–80.

Soutoglou E, Dorn JF, Sengupta K, et al. (2007) Positional stability of single double‐strand breaks in mammalian cells. Nature Cell Biology 9: 675–682.

Symington LS (2016) Mechanism and regulation of DNA end resection in eukaryotes. Critical Reviews in Biochemistry and Molecular Biology 51: 195–212.

Symington LS and Gautier J (2011) Double‐strand break end resection and repair pathway choice. Annual Review of Genetics 45: 247–271.

Vukovic B, Beheshti B, Park P, et al. (2007) Correlating breakage‐fusion‐bridge events with the overall chromosomal instability and in vitro karyotype evolution in prostate cancer. Cytogenetic and Genome Research 116: 1–11.

Weaver BA, Silk AD, Montagna C, et al. (2007) Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer Cell 11: 25–36.

Weinstock DM, Brunet E and Jasin M (2007) Formation of NHEJ‐derived reciprocal chromosomal translocations does not require Ku70. Nature Cell Biology 9: 978–981.

Wray J, Williamson EA, Farrington J, et al. (2010) The transposase domain protein Metnase/SETMAR suppresses chromosomal translocations. Cancer Genetics and Cytogenetics 200: 184–190.

Wray J, Williamson EA, Singh SB, et al. (2013) PARP1 is required for chromosomal translocations. Blood 121: 4359–4365.

Wu S, Shi Y, Mulligan P, et al. (2007) A YY1‐INO80 complex regulates genomic stability through homologous recombination‐based repair. Nature Structural & Molecular Biology 14: 1165–1172.

Zhang Y and Jasin M (2011) An essential role for CtIP in chromosomal translocation formation through an alternative end‐joining pathway. Nature Structural & Molecular Biology 18: 80–84.

Further Reading

Friedberg EC, Elledge SJ, Lehmann AR, et al. (eds) (2014) DNA Repair, Mutagenesis, and Other Responses to DNA Damage, 1st edn. Cold Sprng Harbor, NY: Cold Spring Harbor Laboratory Press.

Mittelman D (ed) (2013) Stress‐Induced Mutagenesis, 1st edn. New York, NY: Springer.

Rowley JD, Le Beau MM and Rabbitts TH (eds) (2015) Chromosomal Translocations and Genome Rearrangements in Cancer, 1st edn. New York, NY: Springer.

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Nickoloff, Jac A(May 2017) Mechanisms of Chromosome Translocations in Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026853]