Brca2 abrogation engages with the alternative lengthening of telomeres via break-induced replication

FEBS J. 2019 May;286(10):1841-1858. doi: 10.1111/febs.14796. Epub 2019 Mar 12.

Abstract

A subset of cancer cells maintains their telomeres without telomerase through the recombination-based alternative lengthening of telomeres (ALT) pathway. Currently, it is not yet clear in what context ALT is induced and how the pathway choice is made. Here, we show that abrogation of Brca2 reinforces break-induced replication (BIR) and engages with ALT pathway. Brca2 depletion in telomerase-null mouse cells alleviated the growth defect, accompanied by telomere elongation, suggesting the induction of ALT. We also found that Brca2-depleted telomerase-null cells exhibited dynamic clustering of telomeres from G2 phase in Promyelocytic Nuclear (PML) bodies. For Brca2-deficient ALT induction, Rad51 was dispensable but Mre11 and Rad52 were required. Congruently, conservative telomeric DNA synthesis was apparent in mitosis, indicating that the absence of Brca2 directed towards Rad52-mediated BIR. Collectively, we propose that Brca2 abrogation can instigate ALT tumourigenesis through the induction of BIR. This study implies that inhibitors of BIR may be useful for BRCA2-associated ALT-type cancers. Assessing ALT features may be considered for the tailored therapy of BRCA2-associated cancers.

Keywords: ALT mouse; Brca2; alternative lengthening of telomeres; break-induced replication.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • BRCA2 Protein / genetics*
  • BRCA2 Protein / metabolism
  • DNA Replication / physiology*
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • G2 Phase
  • MRE11 Homologue Protein / genetics
  • MRE11 Homologue Protein / metabolism
  • Mice, Knockout
  • Mice, Transgenic
  • Rad52 DNA Repair and Recombination Protein / genetics
  • Rad52 DNA Repair and Recombination Protein / metabolism
  • Telomere / genetics*
  • Telomere Shortening / genetics

Substances

  • BRCA2 Protein
  • BRCA2 protein, mouse
  • Mre11a protein, mouse
  • Rad52 DNA Repair and Recombination Protein
  • Rad52 protein, mouse
  • MRE11 Homologue Protein