Processing-challenges generated by clusters of DNA double-strand breaks underpin increased effectiveness of high-LET radiation and chromothripsis

Emil Mladenov, Janapriya Saha, George Iliakis

Research output: Chapter in Book/Report/Conference proceedingChapter

7 Scopus citations

Abstract

Whereas most endogenous and exogenous DNA damaging agents typically generate lesions that are relatively isolated and can be repaired easily, ionizing radiation (IR) also induces clustered lesions causing DNA double strand breaks (DSBs). Moreover, forms of IR characterized by high linear energy transfer (LET) induce not only isolated DSBs but also DSB clusters – multiple DSBs in close proximity -that pose increased risks for the cell. DSB clusters can destabilize chromatin locally and compromise processing of individual DSBs within the cluster. Since the discovery of chromothripsis, a phenomenon whereby multiple DSBs locally generated by a catastrophic event causes genomic rearrangements that feed carcinogenesis, DSB clusters receive increased attention also in the field of cancer. While formation of DSB clusters after exposure to high LET is a direct and inherent consequence of the spatial distribution of the constituting energy deposition events, also called track structure, the sources of local genomic shattering underpinning chromothripsis are under investigation. Notably, many consequences of DSB clusters in the affected genome reflect processing by pathways that have evolved to repair DSBs, but which operate with widely different degrees of fidelity. The molecular underpinnings and the basis of the underlying repair pathway choices that ultimately lead to the observed consequences from DSB clusters remain unknown. We developed a tractable model of DSB clustering that allows direct analysis in cells of the consequences of certain configurations of DSB clusters. We outline the rationale for the development of this model and describe its key characteristics. We summarize results suggesting that DSB clusters compromise the first-line DSB-processing pathways of c-NHEJ and HRR, increasing as a consequence the contribution of alt-EJ, which has high propensity of generating chromosomal rearrangements. The results suggest a mechanism for the increased toxicity of high LET radiation and the extensive genomic rearrangements associated with chromothripsis.

Original languageEnglish (US)
Title of host publicationAdvances in Experimental Medicine and Biology
PublisherSpringer New York LLC
Pages149-168
Number of pages20
DOIs
StatePublished - Jan 1 2018

Publication series

NameAdvances in Experimental Medicine and Biology
Volume1044
ISSN (Print)0065-2598
ISSN (Electronic)2214-8019

Keywords

  • Chromosomal translocations
  • DSB clusters
  • High LET

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Mladenov, E., Saha, J., & Iliakis, G. (2018). Processing-challenges generated by clusters of DNA double-strand breaks underpin increased effectiveness of high-LET radiation and chromothripsis. In Advances in Experimental Medicine and Biology (pp. 149-168). (Advances in Experimental Medicine and Biology; Vol. 1044). Springer New York LLC. https://doi.org/10.1007/978-981-13-0593-1_10