Role of the Topoisomerase IIα Chromatin Tether domain in Nucleosome Binding & Chromosome Segregation
biorxiv(2021)
摘要
Due to the intrinsic nature of DNA replication, replicated genomes retain catenated genomic loci that must be resolved to ensure faithful segregation of sister chromatids in mitosis. Type II DNA Topoisomerase (TopoII) decatenates the catenated genomic DNA through its unique Strand Passage Reaction (SPR). Loss of SPR activity results in anaphase chromosome bridges and formation of Polo-like Kinase Interacting Checkpoint Helicase (PICH)-coated ultra-fine DNA bridges (UFBs) whose timely resolution is required to prevent micronuclei formation. Vertebrates have two TopoII isoforms– TopoIIα and TopoIIβ, that share a conserved catalytic core. However, the essential mitotic function of TopoIIα cannot be compensated by TopoIIβ, due to differences in their catalytically inert C-terminal domains (CTDs). Using genome-edited human cells, we show that specific binding of TopoIIα to methylated histone, tri-methylated H3K27 (H3K27me3), via its Chromatin Tether (ChT) domain within the CTD contributes critically to avoid anaphase UFB formation. Reducing H3K27 methylation prior to mitosis increases UFBs, revealing a requirement for proper establishment of H3K27me3 after DNA replication to facilitate TopoIIα-ChT dependent UFB prevention. We propose that interaction of the TopoIIα-ChT with H3K27me3 is a key factor that ensures the complete resolution of catenated loci to permit faithful chromosome segregation in human cells.
Summary Statement Genomic catenations originating from the DNA replication process must be resolved by DNA Topoisomerase II (TopoII) to permit sister chromatid disjunction. The results show that specific recognition of methylated histone containing chromatin by TopoII is critical for complete resolution of the genome.
### Competing Interest Statement
The authors have declared no competing interest.
* AID
: Auxin inducible degron
Aux
: Auxin
Dox
: Doxycycline
CEN
: Centromere
ChT
: Chromatin Tether
CTD
: C-terminal domain
PICH
: Polo-like kinase interacting checkpoint helicase
SPR
: Strand passage reaction
Tet
: Tetracycline
TopoIIα
: Topoisomerase IIα
TopoIIβ
: Topoisomerase IIβ
UFB
: Ultra-fine DNA bridge
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关键词
nucleosome binding,chromosome segregation
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