Dysregulation of the centrosome induced by BRCA1 deficiency contributes to tissue-specific carcinogenesis

Abstract

Alterations in breast cancer gene 1 (BRCA1), a tumor suppressor gene, increase the risk of breast and ovarian cancers. BRCA1 forms a heterodimer with BRCA1-associated RING domain protein 1 (BARD1) and functions in multiple cellular processes, including DNA repair and centrosome regulation. BRCA1 acts as a tumor suppressor by promoting homologous recombination (HR) repair, and alterations in BRCA1 cause HR deficiency, not only in breast and ovarian tissues but also in other tissues. The molecular mechanisms underlying BRCA1 alteration-induced carcinogenesis remain unclear. Centrosomes are the major microtubule-organizing centers and function in bipolar spindle formation. The regulation of centrosome number is critical for chromosome segregation in mitosis, which maintains genomic stability. BRCA1/BARD1 function in centrosome regulation together with Obg-like ATPase (OLA1) and receptor for activating protein C kinase 1 (RACK1). Cancer-derived variants of BRCA1, BARD1, OLA1, and RACK1 do not interact, and aberrant expression of these proteins results in abnormal centrosome duplication in mammary-derived cells, and rarely in other cell types. RACK1 is involved in centriole duplication in the S phase by promoting polo-like kinase 1 activation by Aurora A, which is critical for centrosome duplication. Centriole number is higher in cells derived from mammary tissues compared with in those derived from other tissues, suggesting that tissue-specific centrosome characterization may shed light on the tissue specificity of BRCA1-associated carcinogenesis. Here, we explored the role of the BRCA1-containing complex in centrosome regulation and the effect of its deficiency on tissue-specific carcinogenesis.

Keywords: BRCA1; HBOC; breast cancer; centrosome; centrosome amplification.

FIGURE 1

Structure of BRCA1 and BARD1. BRCA1 and BARD1 have a RING domain and nuclear export signal (NES) in the N‐terminus and 2 BRCT domains in the C‐terminus. BRCA1 includes a nuclear localization signal (NLS) and a coiled‐coil domain. BARD1 contains ankyrin (ANK) repeats

FIGURE 2

Schematic diagram of the centrosomes. The centrosome consists of mother centriole and daughter centriole, embedded in the pericentriolar matrix (PCM). The PCM contains γ‐tubulin ring complexes required for microtubule nucleation

FIGURE 3

Schematic diagram of the centrosome duplication cycle. The mother and daughter centrioles are disengaged in late mitosis‐early G1 phase. After centriole disengagement, linkers are established between the 2 centrioles. In late G1 phase, a procentriole containing cartwheel is formed at each centriole. The building of the new centriole starts in the early S phase and 1 new daughter centriole forms perpendicularly to each mother centriole during the S phase. The new daughter centriole gradually elongates during the S and G2 phases. In the G2 phase, the 2 centrosomes separate through the dissolution of the linker and move to opposite sides of the cell to form the spindle poles

FIGURE 4

BRCA1 complex. A, The BRCA1‐RACK1 interaction and the effects of the BRCA1 and RACK1 variants. B, BRCA1 complex and abnormal complexes containing variants of BRCA1, BARD1, or OLA1. “N” indicates the N‐terminus. “C” indicates the C‐terminus

FIGURE 5

Regulation of PLK1 activity by RACK1. Under physiological conditions, RACK1 recruits Aurora A to centrosomes, thereby facilitating Aurora A binding to and phosphorylating PLK1 in the S phase. In G2 and M phases, activation of PLK1 is supported by Bora, CEP192, and Furry. Excess RACK1 induces overactivation of PLK1 in the S phase, resulting in premature centriole disengagement and centriole reduplication. Deficiency of RACK1 suppresses centriole duplication due to inadequate activation of PLK1