Loss of pRB causes centromere dysfunction and chromosomal instability.
Chromosome instability (CIN) is a common feature of tumor cells. By monitoring chromosome segregation, we show that depletion of the retinoblastoma protein (pRB) causes rates of missegregation comparable with those seen in CIN tumor cells. The retinoblastoma tumor suppressor is frequently inactivated in human cancers and is best known for its regulation of the G1/S-phase transition. Recent studies have shown that pRB inactivation also slows mitotic progression and promotes aneuploidy, but reasons for these phenotypes are not well understood. Here we describe the underlying mitotic defects of pRB-deficient cells that cause chromosome missegregation. Analysis of mitotic cells reveals that pRB depletion compromises centromeric localization of CAP-D3/condensin II and chromosome cohesion, leading to an increase in intercentromeric distance and deformation of centromeric structure. These defects promote merotelic attachment, resulting in failure of chromosome congression and an increased propensity for lagging chromosomes following mitotic delay. While complete loss of centromere function or chromosome cohesion would have catastrophic consequences, these more moderate defects allow pRB-deficient cells to proliferate but undermine the fidelity of mitosis, leading to whole-chromosome gains and losses. These observations explain an important consequence of RB1 inactivation, and suggest that subtle defects in centromere function are a frequent source of merotely and CIN in cancer.
Manning
Amity L
AL
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Longworth
Michelle S
MS
Dyson
Nicholas J
NJ
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002503:Centromere / Q000235:genetics / Q000378:metabolism*; D043171:Chromosomal Instability / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D020090:Chromosome Segregation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008938:Mitosis / Q000235:genetics; D046912:Multiprotein Complexes / Q000378:metabolism; D009369:Neoplasms / Q000503:physiopathology; D034622:RNA Interference; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D000097722:Cohesins
D000251:Adenosine Triphosphatases; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; D016160:Retinoblastoma Protein; D000097722:Cohesins; C108312:condensin complexes