| Pericentrin is a large coiled-coil protein that forms an elongated scaffold within the pericentriolar material, the protein matrix surrounding the two centrioles that together constitute the centrosome, the principal microtubule organizing center of animal cells. As a structural scaffold, pericentrin anchors and recruits a defined set of pericentriolar material components, including CDK5RAP2, NEDD1, and the gamma-tubulin ring complex, positioning these microtubule-nucleating factors at the centrosome rather than allowing them to diffuse freely in the cytoplasm. Pericentrin-mediated anchoring of gamma-tubulin ring complexes at mitotic centrosomes is specifically required for proper spindle organization, and a pericentrin mutant with diminished binding to the gamma-tubulin complex components GCP2 and GCP3 shows significantly reduced centrosomal aster formation during mitosis, while interphase asters and Ran-mediated, centrosome-independent aster assembly remain largely unaffected, indicating that pericentrin's anchoring function is selectively required for mitotic, centrosome-dependent microtubule organization rather than for microtubule nucleation broadly. Loss of this anchoring mechanism triggers a checkpoint response that prevents mitotic entry and induces apoptotic cell death in a range of cell types, linking pericentrin-dependent centrosome integrity directly to cell cycle progression rather than solely to spindle geometry. Complete absence of pericentrin produces disorganized mitotic spindles and chromosome missegregation, and biallelic loss-of-function mutations in the PCNT gene cause microcephalic osteodysplastic primordial dwarfism type II, a condition marked by severe proportionate short stature and pronounced microcephaly despite near-normal intelligence in most affected individuals. Beyond spindle assembly, pericentrin contributes to centrosome-associated Chk1 recruitment, connecting centrosome integrity to G2/M checkpoint activation in the presence of DNA damage, and disruption of this checkpoint pathway represents one proposed mechanism by which pericentrin loss produces the growth failure characteristic of primordial dwarfism, alongside models implicating direct spindle orientation defects and randomized asymmetric versus symmetric stem cell divisions. Pericentrin overexpression, conversely, produces supernumerary centrosomes and multipolar spindles in fibroblasts, indicating that both loss and excess of pericentrin destabilize normal centrosome number and function. This dual sensitivity to pericentrin dosage, together with its established role as a scaffold-dependent checkpoint regulator rather than a passive structural marker, positions pericentrin as a defined target for researchers studying centrosome-linked growth disorders and the connection between centrosome integrity and genomic stability in cancer. |
