Abstract
PICH is a SNF2 family DNA translocase that binds to ultra-fine DNA bridges (UFBs) in mitosis. Numerous roles for PICH have been proposed from protein depletion experiments, but a consensus has failed to emerge. Here, we report that deletion of PICH in avian cells causes chromosome structural abnormalities, and hypersensitivity to an inhibitor of Topoisomerase II (Topo II), ICRF-193. ICRF-193-treated PICH−/− cells undergo sister chromatid non-disjunction in anaphase, and frequently abort cytokinesis. PICH co-localizes with Topo IIα on UFBs and at the ribosomal DNA locus, and the timely resolution of both structures depends on the ATPase activity of PICH. Purified PICH protein strongly stimulates the catalytic activity of Topo II in vitro. Consistent with this, a human PICH−/− cell line exhibits chromosome instability and chromosome condensation and decatenation defects similar to those of ICRF-193-treated cells. We propose that PICH and Topo II cooperate to prevent chromosome missegregation events in mitosis.
Highlights
PICH is a SNF2 family DNA translocase that binds to ultra-fine DNA bridges (UFBs) in mitosis
Through analysis of chicken cells lacking the PICH protein, we have provided evidence that PICH and Topo IIa functionally cooperate in order to preserve chromosomal integrity during mitosis
Through the complementation of PICH À / À DT40 cells with fluorescently tagged hPICH proteins, we were able to visualize the behaviour of PICH and PICH-K128A during mitosis in vivo
Summary
PICH is a SNF2 family DNA translocase that binds to ultra-fine DNA bridges (UFBs) in mitosis. PICH has the unusual property of acting as a form of DNA ‘tension sensor’, in that it binds more efficiently in vitro to dsDNA that is exposed to stretching forces[12] This has been proposed to explain why PICH decorates UFBs along their entire length irrespective of the stage of anaphase, as UFBs tethered at each end to the separating sister chromatids would be expected to be under tension because of forces exerted by the mitotic spindle[12]. We have generated a PICH À / À human cell line, which displays defects in sister chromatid disjunction These data, coupled with the finding that PICH strongly stimulates the catalytic activity of Topo II in vitro, lead us to propose a model in which PICH and Topo II functionally cooperate in mitosis to ensure faithful chromosome segregation, and to prevent chromosome non-disjunction and polyploidization
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