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Direct roles of human INO80 in chromosomal replication, condensation and segregation suppress genome instability

Direct roles of human INO80 in chromosomal replication, condensation and segregation suppress genome instability

Chromosomal replication, condensation and segregation are central to eukaryotic cell division cycle. Their accurate and efficient execution is not only essential for faithful genome propagation but also critical to maintain genetic stability and prevent development of human diseases such as cancer. Here we show that human INO80(hINO80) chromatin remodeling enzyme plays direct roles in all of these chromosomal processes by dynamically changing its subcellular localization during cell cycle. hINO80, existing primarily within the cytoplasm at G1, associates with chromatin in the nucleus localizing at replication forks during S phase. After brief dissociation from chromatin following DNA replication, hINO80 reassociates with chromatin localizing at condensing chromosomes during G2 phase. As cells enter mitosis, hINO80 associates dominantly with microtubules via interaction with tubulins, and this association is maintained until the mitosis is completed. hINO80 deficiency leads to impaired DNA replication, inefficient chromosome condensation, failure in microtubule assembly, abnormal chromosome segregation such as anaphase bridge, and multinuclear formation due to cytokinesis defect. Further, hINO80-deficient cells exhibit aneuploidy as well as structural chromosome abnormalities, including trans locations, deletions and telomere fusions. These results suggest that a range of the vital chromosomal processes responsible for both genome propagation and stability can be regulated by a single ATP-dependent chromatin remodeler.

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