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Mechanism of tandem duplication formation in BRCA1-mutant cells

Nicholas A Willis1, Richard L Frock2, Francesca Menghi3

  • 1Department of Medicine, Division of Hematology-Oncology and Cancer Research Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.

Nature
|November 24, 2017
PubMed

Insights

BRCA1 deficiency drives the formation of ~10 kilobase tandem duplications by preventing replication fork restart. This tandem duplicator phenotype is a signature of BRCA1-deficient cancers, including breast and ovarian cancers.

Area of Science:

  • Genetics and Genomics
  • Molecular Biology
  • Cancer Research

Background:

  • Microhomology-mediated tandem duplications (MDTs) are prevalent in BRCA1-linked breast cancer.
  • The precise mechanism driving this genomic instability in BRCA1-deficient cancers remains unclear.
  • BRCA1 and BRCA2 proteins play critical roles in DNA repair and genome maintenance.

Purpose of the Study:

  • To elucidate the mechanism underlying the formation of ~10 kilobase tandem duplications associated with BRCA1 deficiency.
  • To investigate the role of BRCA1 and BRCA2 in suppressing tandem duplications at replication fork barriers.
  • To determine if this tandem duplicator phenotype is a general signature of BRCA1-deficient cancers.

Main Methods:

  • Utilized primary mammalian cells to study tandem duplication formation at a site-specific replication fork barrier (Tus-Ter system).
  • Compared the roles of BRCA1 and BRCA2 in suppressing tandem duplications.
  • Investigated the mechanisms of replication restart, bypass, and DNA end joining in BRCA1-mutant cells.
  • Analyzed the association of ~10 kilobase tandem duplications with BRCA1 inactivation in ovarian cancer.

Main Results:

  • BRCA1, but not BRCA2, suppresses tandem duplications at stalled replication forks created by Tus-Ter binding.
  • Tandem duplications in BRCA1-mutant cells arise from replication restart-bypass mechanisms, involving end joining or microhomology-mediated template switching.
  • Solitary DNA ends at Tus-Ter sites suggest misrepair contributes to tandem duplication formation.
  • BRCA1 inactivation is strongly linked to ~10 kilobase tandem duplications in ovarian cancer.

Conclusions:

  • BRCA1 deficiency leads to a tandem duplicator phenotype specifically at stalled replication forks.
  • The mechanism involves impaired replication restart and subsequent DNA repair events.
  • This tandem duplicator phenotype is a potential pan-cancer biomarker for BRCA1 deficiency, extending beyond breast to ovarian cancer.

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