Chromosome Instability: RB Moonlights in Mitosis

RESEARCH HIGHLIGHTS CHROMOSOME INSTABILITY cohesion, which leads to chromosome segregation errors and CIN. So, is this role of RB1 important for RB moonlights in mitosis its function as a tumour suppressor? Coschi et al. used Rb1ΔL/ΔL mice that Loss of the retinoblastoma (RB) Manning and colleagues used express a mutant RB1 that cannot bind tumour suppressor pathway com- RNA interference to down- condensin II complexes to test this. monly occurs in tumours and is asso- regulate RB1 expression in TERT- The authors showed that the increased ciated with chromosome instability immortalized RPE1 cells (which are lagging chromosomes and centro- (CIN). The RB pathway is famous for diploid epithelial cells) and found that meric fusions observed in MEFs from its role in mediating G1/S cell cycle the loss of RB1 induces aneuploidy these mice were not the result of loss checkpoint control, but can this role and chromosome missegregation. of G1/S cell cycle checkpoint control. alone account for its tumour suppres- Knock down of RB1 did not affect Live imaging of these MEFs revealed sive function? proliferation but increased the mitotic the same mitotic defects, which they Evidence suggests that loss of index by twofold. In particular, the showed caused aneuploidy from either the RB pathway affects mitosis, so authors found a high proportion of an abrupt termination of the delay Van Harn and colleagues arrested cells in prometaphase, indicating that at metaphase (probably caused by mouse embryonic fibroblasts in loss of RB1 delayed mitotic progres- chromosome breakage) or a failure to which the three Rb family members sion. On further analysis, the authors complete mitosis (which generated were ablated (TKO-MEFs) in G2 by observed increased inter-centromeric binucleated cells). Condensin II sub- serum starvation. This induced the distance between sister chromatids, units were also improperly loaded cyclin-dependent kinase inhibitor defects in chromosome congression, onto chromatin. The expression of the p21, produced double-strand DNA sister kinetochore orientation and RB1 mutant reduced the latency of breaks and activated the homologous alignment on the metaphase plate. tumour initiation in Rb1ΔL/ΔL;Trp53–/– recombination repair pathway. The authors proposed that these and Rb1ΔL/ΔL;Trp53+/– mice. Moreover, Inhibiting DNA damage response mitotic defects might originate from the tumours were more aggressive, (DDR) kinases accelerated cell cycle a defect in the centromere structure, there was a higher incidence of metas- re-entry and progression into mitosis which is regulated by the cohesin tases and a higher proportion of mice after release from serum starvation and condensin complexes. They with multiple tumours. By comparing and downregulated p21 expression. found that chromatin association of thymic lymphoma cells from Rb1ΔL/ΔL; These data indicate that serum- RAD21 — a subunit of the cohesin Trp53–/– and Trp53–/– mice the authors starved RB pathway-deficient cells complex — was reduced in mitotic found that whole and segmental accumulate DNA damage during cells lacking RB1, suggesting that its chromosome gains and losses were progression through the preceding loss impairs the loading or mainte- increased in the lymphoma cells that S phase and thereby activate DDR nance of the cohesin complex at the expressed mutant RB1, suggesting that pathways. Moreover, metaphase centromere. the accompanying CIN could account spreads of TKO-MEFs showed RBF1, the Drosophila melanogaster for the reduced tumour latency. defects in centromeric sister chro- RB homologue, interacts with the Together, these data suggest that matid cohesion and more chromatid condensin II subunit CAP-D3. the CIN resulting from the inability breaks than in controls, suggesting Adding to these findings, Manning of RB1 to maintain sister chromatid damage persists in mitosis. Consistent and colleagues showed that RBF1 also cohesion promotes tumorigenesis with this, the authors showed that promotes cohesin complex loading and that this is an important function serum-starved TKO-MEFs that onto DNA in D. melanogaster. In addi- of RB1 as a tumour suppressor. re-entered the cell cycle after serum tion they found that CAP-D3 loading Gemma K. Alderton addition had increased copy number on chromatin was decreased in RB1- alterations. Sister chromatid cohesion deficient RPE1 cells and that knock ORIGINAL RESEARCH PAPERS van Harn, T. et al. Loss of RB proteins causes genomic instability in is initiated during S phase by the down of CAP-D3 caused similar the absence of mitogenic signalling. Genes Dev. 24, cohesin complex, and although mitotic defects in RPE1 cells to those 1377–1388 (2010) | Manning, A. L. et al. Loss of pRB the authors did not find evidence of RB1 knockdown. Interestingly, con- causes centromere dysfunction and chromsome instability. Genes Dev. 24, 1364–1376 (2010) | of improper loading of the cohesin densin II complexes are enriched at the Coschi, C. H. et al. Mitotic chromosome complex they suggested that this centromeres of mitotic chromosomes, condensation mediated by the retinoblastoma process might be defective when the suggesting that RB1 loss causes defec- protein is tumor suppressive. Genes Dev. 24, 1351–1363 (2010) RB pathway is inactivated. tive centromeric condensation and NATURE REVIEWS | CANCER VOLUME 10 | AUGUST 2010 © 2010 Macmillan Publishers Limited. All rights reserved.

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