Mechanisms Driving Chromosomal Translocations: Lost in Time and Space

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2021 Jun 9

PMID 34103687

Citations 18

Authors

Dale A Ramsden

Andre Nussenzweig

Affiliations

Soon will be listed here.

Abstract

Translocations arise when an end of one chromosome break is mistakenly joined to an end from a different chromosome break. Since translocations can lead to developmental disease and cancer, it is important to understand the mechanisms leading to these chromosome rearrangements. We review how characteristics of the sources and the cellular responses to chromosome breaks contribute to the accumulation of multiple chromosome breaks at the same moment in time. We also discuss the important role for chromosome break location; how translocation potential is impacted by the location of chromosome breaks both within chromatin and within the nucleus, as well as the effect of altered mobility of chromosome breaks. A common theme in work addressing both temporal and spatial contributions to translocation is that there is no shortage of examples of factors that promote translocation in one context, but have no impact or the opposite impact in another. Accordingly, a clear message for future work on translocation mechanism is that unlike normal DNA metabolic pathways, it isn't easily modeled as a simple, linear pathway that is uniformly followed regardless of differing cellular contexts.

Citing Articles

Unravelling single-cell DNA replication timing dynamics using machine learning reveals heterogeneity in cancer progression.

Josephides J, Chen C Nat Commun. 2025; 16(1):1472.

PMID: 39922809 PMC: 11807193. DOI: 10.1038/s41467-025-56783-0.

Transcriptional regulation of the non-homologous end joining gene Ligase IV by an intronic regulatory element directs thymocyte development.

Estrada M, Collins P, Estrada M, Gebhardt C, Gebhardt C, Salem M Res Sq. 2025; .

PMID: 39866872 PMC: 11760251. DOI: 10.21203/rs.3.rs-5718046/v1.

A comparative analysis of planarian genomes reveals regulatory conservation in the face of rapid structural divergence.

Ivankovic M, Brand J, Pandolfini L, Brown T, Pippel M, Rozanski A Nat Commun. 2024; 15(1):8215.

PMID: 39294119 PMC: 11410931. DOI: 10.1038/s41467-024-52380-9.

DNA double-strand break movement in heterochromatin depends on the histone acetyltransferase dGcn5.

Kendek A, Sandron A, Lambooij J, Colmenares S, Pociunaite S, Gooijers I Nucleic Acids Res. 2024; 52(19):11753-11767.

PMID: 39258543 PMC: 11514474. DOI: 10.1093/nar/gkae775.

Distinct functions of PAXX and MRI during chromosomal end joining.

Cisneros-Aguirre M, Lopezcolorado F, Ping X, Chen R, Stark J bioRxiv. 2024; .

PMID: 39229097 PMC: 11370355. DOI: 10.1101/2024.08.21.607864.

References

Li Y, Roberts N, Wala J, Shapira O, Schumacher S, Kumar K . Patterns of somatic structural variation in human cancer genomes. Nature. 2020; 578(7793):112-121. PMC: 7025897. DOI: 10.1038/s41586-019-1913-9. View

Zhang F, Khajavi M, Connolly A, Towne C, Batish S, Lupski J . The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans. Nat Genet. 2009; 41(7):849-53. PMC: 4461229. DOI: 10.1038/ng.399. View

Sakofsky C, Malkova A . Break induced replication in eukaryotes: mechanisms, functions, and consequences. Crit Rev Biochem Mol Biol. 2017; 52(4):395-413. PMC: 6763318. DOI: 10.1080/10409238.2017.1314444. View

Sudmant P, Rausch T, Gardner E, Handsaker R, Abyzov A, Huddleston J . An integrated map of structural variation in 2,504 human genomes. Nature. 2015; 526(7571):75-81. PMC: 4617611. DOI: 10.1038/nature15394. View

Lee K, Zhang Y, Lee S . Saccharomyces cerevisiae ATM orthologue suppresses break-induced chromosome translocations. Nature. 2008; 454(7203):543-6. DOI: 10.1038/nature07054. View

Richardson C, Moynahan M, Jasin M . Double-strand break repair by interchromosomal recombination: suppression of chromosomal translocations. Genes Dev. 1998; 12(24):3831-42. PMC: 317271. DOI: 10.1101/gad.12.24.3831. View

Zhang Y, McCord R, Ho Y, Lajoie B, Hildebrand D, Simon A . Spatial organization of the mouse genome and its role in recurrent chromosomal translocations. Cell. 2012; 148(5):908-21. PMC: 3320767. DOI: 10.1016/j.cell.2012.02.002. View

Vilenchik M, Knudson A . Endogenous DNA double-strand breaks: production, fidelity of repair, and induction of cancer. Proc Natl Acad Sci U S A. 2003; 100(22):12871-6. PMC: 240711. DOI: 10.1073/pnas.2135498100. View

Lobrich M, Cooper P, Rydberg B . Joining of correct and incorrect DNA ends at double-strand breaks produced by high-linear energy transfer radiation in human fibroblasts. Radiat Res. 1998; 150(6):619-26. View

10.

Brunet E, Jasin M . Induction of Chromosomal Translocations with CRISPR-Cas9 and Other Nucleases: Understanding the Repair Mechanisms That Give Rise to Translocations. Adv Exp Med Biol. 2018; 1044:15-25. PMC: 6333474. DOI: 10.1007/978-981-13-0593-1_2. View

11.

Morton L, Karyadi D, Stewart C, Bogdanova T, Dawson E, Steinberg M . Radiation-related genomic profile of papillary thyroid carcinoma after the Chernobyl accident. Science. 2021; 372(6543). PMC: 9022889. DOI: 10.1126/science.abg2538. View

12.

Ramsden D, Gellert M . Formation and resolution of double-strand break intermediates in V(D)J rearrangement. Genes Dev. 1995; 9(19):2409-20. DOI: 10.1101/gad.9.19.2409. View

13.

Ramsden D, Paull T, Gellert M . Cell-free V(D)J recombination. Nature. 1997; 388(6641):488-91. DOI: 10.1038/41351. View

14.

Pannunzio N, Lieber M . Concept of DNA Lesion Longevity and Chromosomal Translocations. Trends Biochem Sci. 2018; 43(7):490-498. PMC: 6014902. DOI: 10.1016/j.tibs.2018.04.004. View

15.

Sternberg S, Redding S, Jinek M, Greene E, Doudna J . DNA interrogation by the CRISPR RNA-guided endonuclease Cas9. Nature. 2014; 507(7490):62-7. PMC: 4106473. DOI: 10.1038/nature13011. View

16.

Richardson C, Ray G, DeWitt M, Curie G, Corn J . Enhancing homology-directed genome editing by catalytically active and inactive CRISPR-Cas9 using asymmetric donor DNA. Nat Biotechnol. 2016; 34(3):339-44. DOI: 10.1038/nbt.3481. View

17.

Stracker T, Petrini J . The MRE11 complex: starting from the ends. Nat Rev Mol Cell Biol. 2011; 12(2):90-103. PMC: 3905242. DOI: 10.1038/nrm3047. View

18.

Bredemeyer A, Huang C, Walker L, Bassing C, Sleckman B . Aberrant V(D)J recombination in ataxia telangiectasia mutated-deficient lymphocytes is dependent on nonhomologous DNA end joining. J Immunol. 2008; 181(4):2620-5. PMC: 3598579. DOI: 10.4049/jimmunol.181.4.2620. View

19.

Chen C, Kolodner R . Gross chromosomal rearrangements in Saccharomyces cerevisiae replication and recombination defective mutants. Nat Genet. 1999; 23(1):81-5. DOI: 10.1038/12687. View

20.

Gunn A, Bennardo N, Cheng A, Stark J . Correct end use during end joining of multiple chromosomal double strand breaks is influenced by repair protein RAD50, DNA-dependent protein kinase DNA-PKcs, and transcription context. J Biol Chem. 2011; 286(49):42470-42482. PMC: 3234933. DOI: 10.1074/jbc.M111.309252. View