Lee MiYoung, Venkitaraman Ashok R
a University of Cambridge ; Medical Research Council Cancer Unit; Hutchison/MRC Research Center ; Cambridge , UK.
Cell Cycle. 2014;13(16):2554-63. doi: 10.4161/15384101.2014.942204.
Defects in the completion of cell division by cytokinesis have long been proposed to foster carcinogenesis by engendering chromosome instability, but few tumor suppressor mechanisms controlling this process have so far been identified. Here, we identify a carboxyl (C)-terminal region of the high-mobility group protein HMG20b that is essential for cytokinesis, and report that it is inactivated by a cancer-associated mutation. We find that a C-terminal region of HMG20b spanning residues 173-317 is necessary and sufficient not only for its localization to cytokinetic structures, but also for its interaction with the tumor suppressor BRCA2, implicated in the abscission step of cytokinesis. Indeed, expression of this C-terminal HMG20b region suffices to restore cytokinesis in HMG20b-depleted cells. The non-conservative substitution of HMG20b residue Ala247 with Pro, reported in human lung cancer, disrupts these activities of HMG20b, impairing cytokinesis in a trans-dominant manner. Our findings provide fresh insight into the mechanism by which the HMG20b-BRCA2 complex controls mitotic cell division, and implicate heterozygous HMG20b mutations affecting cytokinesis regulation in the genesis of human cancers.
长期以来，人们一直认为细胞分裂末期通过胞质分裂完成过程中的缺陷会因导致染色体不稳定而促进癌症发生，但迄今为止，很少有控制这一过程的肿瘤抑制机制被发现。在此，我们鉴定出高迁移率族蛋白HMG20b的一个羧基（C）末端区域，它对胞质分裂至关重要，并报告该区域因一个与癌症相关的突变而失活。我们发现，HMG20b跨越第173至317位残基的C末端区域不仅对其定位于胞质分裂结构是必要且充分的，而且对其与肿瘤抑制因子BRCA2的相互作用也是必要且充分的，BRCA2参与胞质分裂的切割步骤。事实上，该C末端HMG20b区域的表达足以在HMG20b缺失的细胞中恢复胞质分裂。在人类肺癌中报道的HMG20b第247位残基由丙氨酸非保守替换为脯氨酸，破坏了HMG20b的这些活性，以反式显性方式损害胞质分裂。我们的发现为HMG20b - BRCA2复合物控制有丝分裂细胞分裂的机制提供了新的见解，并表明影响胞质分裂调控的杂合HMG20b突变与人类癌症的发生有关。
