The Role for the DSB response pathway in regulating chromosome translocations

Rajib Ghosh, Debamitra Das, Sonia Franco

Research output: Chapter in Book/Report/Conference proceedingChapter

6 Scopus citations


In response to DNA double strand breaks (DSB), mammalian cells activate the DNA Damage Response (DDR), a network of factors that coordinate their detection, signaling and repair. Central to this network is the ATM kinase and its substrates at chromatin surrounding DSBs H2AX, MDC1 and 53BP1. In humans, germline inactivation of ATM causes Ataxia Telangiectasia (A-T), an autosomal recessive syndrome of increased proneness to hematological malignancies driven by clonal chromosomal translocations. Studies of cancers arising in A-T patients and in genetically engineered mouse models (GEMM) deficient for ATM and its substrates have revealed complex, multilayered roles for ATM in translocation suppression and identified functional redundancies between ATM and its substrates in this context. “Programmed” DSBs at antigen receptor loci in developing lymphocytes employ ubiquitous DDR factors for signaling and repair and have been particularly useful for mechanistic studies because they are region-specific and can be monitored in vitro and in vivo. In this context, murine thymocytes deficient for ATM recapitulate the molecular events that lead to transformation in T cells from A-T patients and provide a widely used model to study the mechanisms that suppress RAG recombinase-dependent translocations. Similarly, analyses of the fate of Activation induced Cytidine Deaminase (AID)-dependent DSBs during mature B cell Class Switch Recombination (CSR) have defined the genetic requirements for end-joining and translocation suppression in this setting. Moreover, a unique role for 53BP1 in the promotion of synapsis of distant DSBs has emerged from these studies.

Original languageEnglish (US)
Title of host publicationAdvances in Experimental Medicine and Biology
PublisherSpringer New York LLC
Number of pages23
StatePublished - 2018

Publication series

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


  • AID
  • ATM
  • Chromosomal translocation
  • Class switch recombination
  • RAG
  • V(D)J recombination

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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