| Autor: |
Sethi SC; Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Shrestha RL; Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Balachandra V; Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Durairaj G; Department of Biological Chemistry, School of Medicine, University of California, Irvine, California, USA., Au WC; Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Nirula M; Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Karpova TS; Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Kaiser P; Department of Biological Chemistry, School of Medicine, University of California, Irvine, California, USA., Basrai MA; Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. |
| Abstrakt: |
Restricting the localization of evolutionarily conserved histone H3 variant CENP-A to the centromere is essential to prevent chromosomal instability (CIN), an important hallmark of cancers. Overexpressed CENP-A mislocalizes to non-centromeric regions and contributes to CIN in yeast, flies, and human cells. Centromeric localization of CENP-A is facilitated by the interaction of Mis18β with CENP-A specific chaperone HJURP. Cellular levels of Mis18β are regulated by β-transducin repeat containing protein (β-TrCP), an F-box protein of SCF (Skp1, Cullin, F-box) E3-ubiquitin ligase complex. Here, we show that defects in β-TrCP-mediated proteolysis of Mis18β contributes to the mislocalization of endogenous CENP-A and CIN in a triple-negative breast cancer (TNBC) cell line, MDA-MB-231. CENP-A mislocalization in β-TrCP depleted cells is dependent on high levels of Mis18β as depletion of Mis18β suppresses mislocalization of CENP-A in these cells. Consistent with these results, endogenous CENP-A is mislocalized in cells overexpressing Mis18β alone. In summary, our results show that β-TrCP-mediated degradation of Mis18β prevents mislocalization of CENP-A and CIN. We propose that deregulated expression of Mis18β may be one of the key mechanisms that contributes to chromosome segregation defects in cancers. |
