Major finding: BRCA1 is required for DNA condensation and satellite repression.
Impact: This work establishes a key mechanism of tumor suppression by BRCA1.
Concept: Decreased Ub-H2A underlies the cellular consequences of BRCA1 mutation.
The increased risk of breast and ovarian cancer caused by mutation of BRCA1 has been attributed to increased genomic instability, presumably due to impaired homologous recombination. However, cancer-predisposing mutations in BRCA1 frequently compromise its E3 ubiquitin ligase activity, which is not required for homologous recombination. Zhu and colleagues demonstrate that increased genomic instability caused by BRCA1 loss is due to loss of constitutive heterochromatin and abnormal expression of highly repetitive DNA elements. The authors initially noted that targeted deletion of Brca1 in murine neural stem cells led to altered heterochromatin structure corresponding with diminished levels of histone H2A ubiquitination (Ub-H2A) and elevated expression of normally silenced major and minor satellite repeats. BRCA1 was enriched at satellite DNA regions in both mouse and human cells, and BRCA1 ubiquitin ligase activity was specifically required for satellite repression and accumulation of Ub-H2A at these loci. Further, ectopic expression of Ub-H2A restored proliferation and satellite DNA repression in BRCA1-deficient cells, suggesting that H2A is likely the principal substrate of BRCA1 involved in establishment of heterochromatic foci and normal cell growth. Importantly, aberrant satellite DNA derepression was observed in both Brca1-deficient murine mammary tumors and breast tumors of women carrying BRCA1 mutations. Forced expression of satellite DNA induced the same mitotic and DNA repair defects observed following BRCA1 loss, indicating that derepression of these transcripts underlies the genomic instability caused by BRCA1 mutation. These findings clarify the mechanism of tumor suppression by BRCA1 and suggest that satellite DNA expression may have diagnostic applications in breast cancer.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details.