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DNA deaminases induce break-associated mutation showers with implication of APOBEC3B and 3A in breast cancer kataegis

Benjamin Jm Taylor1, Serena Nik-Zainal, Yee Ling Wu

  • 1Protein and Nucleic Acid Chemistry Division , Medical Research Council Laboratory of Molecular Biology , Cambridge , United Kingdom.

Elife
|April 20, 2013
PubMed

Insights

Breast cancer genomes show mutation clusters called kataegis, caused by AID/APOBEC enzymes acting on DNA near breaks. This research implicates APOBEC3B/A in breast cancer hypermutation.

Area of Science:

  • Genomics
  • Molecular Biology
  • Cancer Research

Background:

  • Breast cancer genomes exhibit unique mutation patterns known as kataegis.
  • Kataegis involves clustered, same-strand substitutions at C:G pairs within large genomic regions.
  • These regions are often associated with DNA rearrangements.

Purpose of the Study:

  • To investigate the mechanism underlying kataegis formation in breast cancer.
  • To determine the role of AID/APOBEC enzymes in kataegis.
  • To identify specific APOBEC family members involved in breast cancer hypermutation.

Main Methods:

  • Replicating cancer-like kataegis by expressing AID/APOBEC deaminases in yeast.
  • Analyzing the dependence of kataegis on uracil excision and abasic site generation.
  • Inducing localized kataegis using I-SceI-induced DNA breaks.
  • Comparing genome-wide APOBEC3-catalyzed deamination patterns in yeast with breast cancer kataegic mutations.

Main Results:

  • Kataegis can be generated by AID/APOBEC-catalyzed cytidine deamination near DNA breaks.
  • Yeast models recapitulated kataegis, dependent on uracil excision and strand breakage.
  • APOBEC3B and APOBEC3A showed mutational signatures most similar to breast cancer kataegis.
  • Expression and functional assays supported the role of APOBEC3B/A in breast cancer hypermutation.

Conclusions:

  • AID/APOBEC enzymes, particularly APOBEC3B/A, are implicated in the formation of kataegis in breast cancer.
  • The mechanism involves cytidine deamination on single-stranded DNA exposed during DNA break resection.
  • This study provides insights into the molecular mechanisms driving kataegis and breast cancer hypermutation.
Keywords:
AID/APOBECsCancerCytidine deaminationDNA deaminationHumanHypermutationKataegisS. cerevisiae

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