Poster Presentation 26th Lorne Cancer Conference 2014

The BRCT domains of BARD1 are essential for maintenance of telomere integrity and antagonized by cancer-associated BARD1 isoforms (#291)

Maxim Pilyugin 1 , Magdalena Ratajska 2 , Irmgard Irminger-Finger 1 3
  1. Molecular Gynecology and Obstetrics Laboratory, University Hospitals Geneva, Switzerland, Geneva, Switzerland
  2. Department of Biology and Genetics, edical University of Gdansk, Gdansk, Poland
  3. Centre for Cell Therapy and Regenerative Medicine, University of Western Australia, Perth, Australia

BARD1 has tumor suppressor functions by binding to BRCA1 and to p53 via RING finger and ankyrin repeats, respectively[1]. The BARD1-BRCA1 dimer has E3 ligase activity[2], and the BARD1-p53 interaction promotes apoptosis[3]. The C-terminus of BARD1 is binding to many proteins that are targets of the BRCA1-BARD1 ubiquitin ligase, and expression of N-terminally truncated RING-less BARD1 isoforms was correlated with poor prognosis in various cancers, consistent with their oncogenic functions by antagonistic binding to target proteins[4-6].

We performed interaction assays, which showed that the BARD1 BRCT domains interact with the telomere binding protein TRF2 and are critically involved in telomere maintenance. Overexpression of BARD1 or BRCA1 leads to TRF2 ubiquitination and degradation, suggesting that TRF2 presents a novel target of the BARD1-BRCA1 E3 ubiquitination ligase. The repression of BARD1 or BRCA1 leads to alterations of telomere structures and length. Similar telomeric malfunction was observed by in vitro overexpression of a cancer-associated BARD1 isoform that lacks the BRCA1-interacting RING finger and the ankyrin repeats, but retains the BRCT domains.

Furthermore, we observed distinct telomeric abnormalities in lymphocytes of patients with a BARD1 germline mutation, a frame shift deletion that translates into a truncated protein lacking the BRCT domains. Lymphocytes of a carrier of a BRCA1 mutation that disrupts the BARD1-BRCA1 interaction show similar defects of telomere structures. These in vitro and in vivo observations suggest that BRCA1 and BARD1, via the BARD1 BRCT domains, play distinct roles in maintaining telomere integrity in a dosage dependent manner. We conclude that the correct dose of BARD1 and/or its BRCT domains is critically important for maintaining telomere integrity. 

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