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RAG-induced DNA lesions activate proapoptotic BIM to suppress lymphomagenesis in p53-deficient mice

Alex R D Delbridge1, Swee Heng Milon Pang2, Cassandra J Vandenberg2

  • 1The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia strasser@wehi.edu.au alex.delbridge@biogen.com.

The Journal of Experimental Medicine
|September 14, 2016
PubMed

Insights

The BH3-only protein BIM triggers apoptosis in response to DNA damage, acting independently of p53. Loss of BIM accelerates lymphoma in p53-deficient mice, highlighting a parallel tumor suppressor pathway.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Immunology

Background:

  • Neoplastic transformation involves oncogenic lesions driving uncontrolled cell growth and resistance to cell death.
  • DNA damage typically induces apoptosis via p53-mediated pathways, involving PUMA and NOXA.
  • However, p53-independent apoptotic pathways are implicated in tumor suppression, especially in p53-deficient cancers.

Purpose of the Study:

  • To investigate p53-independent apoptotic pathways activated by oncogenic DNA lesions.
  • To determine the role of the BH3-only protein BIM in apoptosis triggered by DNA damage.
  • To explore the therapeutic potential of BIM-mediated pathways in p53-deficient cancers.

Main Methods:

  • Utilized p53-deficient mouse models to assess lymphoma development.
  • Investigated the impact of BIM deficiency on tumor susceptibility.
  • Examined the role of RAG1/2-mediated gene rearrangement in DNA damage-induced apoptosis.

Main Results:

  • Loss of BIM accelerated lymphoma development in p53-deficient mice.
  • Concomitant loss of RAG1/2-mediated gene rearrangement negated the effect of BIM deficiency.
  • This indicates BIM is crucial for apoptosis induced by DNA lesions from antigen receptor gene rearrangement.

Conclusions:

  • BIM acts as a critical mediator of apoptosis in response to oncogenic DNA lesions, functioning independently of p53.
  • A BIM-mediated tumor suppressor pathway operates in parallel to the p53 pathway.
  • This pathway remains active in p53-deficient cancers, offering potential therapeutic targets.

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