Suv420 enrichment at the centromere limits Aurora B localization and function

Abstract

Centromere structure and function are defined by the epigenetic modification of histones at centromeric and pericentromeric chromatin. The constitutive heterochromatin found at pericentromeric regions is highly enriched for H3K9me3 and H4K20me3. While mis-expression of the methyltransferase enzymes, Suv39 and Suv420, that regulate these marks are common in disease, the consequences of such changes are not well understood. Our data show that increased centromere localization of Suv39 and Suv420 suppress centromere transcription and compromise localization of the mitotic kinase Aurora B: decreasing microtubule dynamics and compromising chromosome alignment and segregation. We find that inhibition of Suv420 methyltransferase activity partially restores Aurora B localization to centromeres and that restoration of the Aurora B-containing CPC to the centromere is sufficient to suppress mitotic errors that result when Suv420/H4K20me3 is enriched at centromeres. Consistent with a role for Suv39 and Suv420 in negatively regulating Aurora B, high expression of these enzymes corresponds with increased sensitivity to Aurora kinase inhibition in cancer cells suggesting that increased H3K9 and H4K20 methylation may be an underappreciated source of chromosome missegregation in cancer.

Methylated histones on mitotic chromosomes promote topoisomerase IIα function for high fidelity chromosome segregation

“… 29 A recent study showed that loss of H4K20me3 reduced Aurora B activity at centromeres. 30 Although this remains to be tested, it is possible that TopoIIα regulates Aurora B recruitment by binding to centromeric nucleosomes containing H4K20me3. It will also be important to test if H3K27me3 contributes to centromeric Aurora B activity.…”

Determinants of Aurora kinase B inhibitor sensitivity in small cell lung cancer

“…RB interacts with SUV420H, and the defects in histone methylation, cohesin binding, and CIN are reversed by overexpression of SUV420H in RB-deficient cells ( 11 , 13 ). Importantly, a recent study showed that AURKB is recruited to kinetochores when SUV420H is inhibited and, at kinetochores, helps prevent chromosome misalignments and missegregations ( 14 ). Lastly, RB loss increases activity of the transcription factor E2F1, which promotes AURKB gene expression ( 15 ).…”

Histone 4 lysine 20 tri-methylation: a key epigenetic regulator in chromatin structure and disease

“…Nonetheless, the roles of KMT5C and H4K20me3 in tumorigenesis are clearly context dependent. Expression data from The Cancer Genome Atlas (TCGA) indicates that KMT5C is highly expressed in cancers ( Herlihy et al, 2021 ). And, increased expression of H4K20me3 was reported in esophageal squamous cell carcinoma tumor tissues ( Zhou et al, 2019 ) and in pancreatic cancer, where KMT5C is reported to favor mesenchymal identity, while KMT5C knockdown decreased stemness and increased drug sensitivity ( Viotti et al, 2018 ).…”