Mitotic chromosome condensation mediated by the retinoblastoma protein is tumor-suppressive

Abstract

Condensation and segregation of mitotic chromosomes is a critical process for cellular propagation, and, in mammals, mitotic errors can contribute to the pathogenesis of cancer. In this report, we demonstrate that the retinoblastoma protein (pRB), a well-known regulator of progression through the G1 phase of the cell cycle, plays a critical role in mitotic chromosome condensation that is independent of G1-to-S-phase regulation. Using gene targeted mutant mice, we studied this aspect of pRB function in isolation, and demonstrate that it is an essential part of pRB-mediated tumor suppression. Cancer-prone Trp53 À/À mice succumb to more aggressive forms of cancer when pRB's ability to condense chromosomes is compromised. Furthermore, we demonstrate that defective mitotic chromosome structure caused by mutant pRB accelerates loss of heterozygosity, leading to earlier tumor formation in Trp53 +/À mice. These data reveal a new mechanism of tumor suppression, facilitated by pRB, in which genome stability is maintained by proper condensation of mitotic chromosomes.[Keywords: Cohesion; condensation; chromosome instability; cell cycle; chromatin] Supplemental material is available at http://www.genesdev.org.

Cyclin E2 induces genomic instability by mechanisms distinct from cyclin E1

“…Inactivation of Rb, p107 and p130 leads to an increase in the number of lagging chromosomes, compromised chromosome condensation, and an increase in chromosome breaks. [40][41][42] The effects of cyclin E2 overexpression shown here are similar to the effects of pocket protein inactivation. This is to be expected, since deregulation of cyclin E2 and consequent deregulation of CDK2 activity in G 2 /M will functionally inactivate the pocket proteins.…”

Mitotic progression following DNA damage enables pattern recognition within micronuclei

“…The pBABE-H2B-GFP plasmid was a gift from Fred Dick (Addgene plasmid #26790) 32 and retrovirus was created using standard protocols and introduced into MCF10A cells expressing mCherry-cGAS. Dual mCherry/GFP positive cells were isolated by cell sorting and seeded onto 35mm Mattek dishes (Mattek).…”

Expression of the kinetochore protein Hec1 during the cell cycle in normal and cancer cells and its regulation by the pRb pathway

“…In starvation experiments, observed in RB or RB silenced cells. 33,34,36,37 In this scenario, Hec1 overexpression may contribute to the reported capacity of pRb depleted cells to undergo chromosome missegregation as a consequence of defects in centromere/kinetochore structure that are responsible for kinetochore-microtubule misattachments, 38 such as merotelic attachments. 6,39 Consistently, recent work has demonstrated that loss of pRB causes centromere dysfunction associated with premature loss of centromeric cohesion, impaired localization of the condensin II subunit CAP-D3 to centromeres and formation of lagging chromosomes at anaphase.…”