Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA.
Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA.
Mol Cell. 2014 Mar 20;53(6):993-1004. doi: 10.1016/j.molcel.2014.01.032. Epub 2014 Mar 6.
Chromosome instability (CIN), a common feature of solid tumors, promotes tumor evolution and increases drug resistance during therapy. We previously demonstrated that loss of the retinoblastoma protein (pRB) tumor suppressor causes changes in centromere structure and generates CIN. However, the mechanism and significance of this change was unclear. Here, we show that defects in cohesion are key to the pRB loss phenotype. pRB loss alters H4K20 methylation, a prerequisite for efficient establishment of cohesion at centromeres. Changes in cohesin regulation are evident during S phase, where they compromise replication and increase DNA damage. Ultimately, such changes compromise mitotic fidelity following pRB loss. Remarkably, increasing cohesion suppressed all of these phenotypes and dramatically reduced CIN in cancer cells lacking functional pRB. These data explain how loss of pRB undermines genomic integrity. Given the frequent functional inactivation of pRB in cancer, conditions that increase cohesion may provide a general strategy to suppress CIN.
染色体不稳定性（CIN）是实体瘤的常见特征，它在治疗过程中促进肿瘤进化并增加药物耐药性。我们之前证明，视网膜母细胞瘤蛋白（pRB）抑癌基因的缺失会导致着丝粒结构发生变化，并产生 CIN。然而，这种变化的机制和意义尚不清楚。在这里，我们表明着丝粒结构的缺陷是关键的 pRB 缺失表型。pRB 缺失改变了 H4K20 甲基化，这是在着丝粒处建立有效着丝粒的前提。在 S 期，黏合蛋白的调节发生变化，这会损害复制并增加 DNA 损伤。最终，这些变化会影响 pRB 缺失后的有丝分裂保真度。值得注意的是，增加黏合可抑制所有这些表型，并显著降低缺乏功能性 pRB 的癌细胞中的 CIN。这些数据解释了 pRB 的缺失如何破坏基因组的完整性。鉴于 pRB 在癌症中的功能经常被抑制，增加黏合的条件可能为抑制 CIN 提供一种通用策略。
