Plaster N, Sonntag C, Busse C E, Hammerschmidt M
Georges-Köhler-Laboratory, Max-Planck Institute of Immunobiology, Stuebeweg 51, 79108 Freiburg, Germany.
Cell Death Differ. 2006 Feb;13(2):223-35. doi: 10.1038/sj.cdd.4401747.
Cell culture work has identified the tumor suppressor p53 as a component of the S-phase checkpoint control system, while in vivo studies of this role of p53 in whole-vertebrate systems were limited. Here, we describe zebrafish mutants in the DNA polymerase delta catalytic subunit 1, based on the positional cloning of the flathead (fla) gene. fla mutants display specific defects in late proliferative zones, such as eyes, brain and cartilaginous elements of the visceral head skeleton, where cells display compromised DNA replication, followed by apoptosis, and partial or complete loss of affected tissues. Antisense-mediated knockdown of p53 in fla mutants leads to a striking rescue of all phenotypic traits, including completion of replication, survival of cells, and normal differentiation and tissue formation. This indicates that under replication-compromised conditions, the p53 branch of the S-phase checkpoint is responsible for eliminating stalled cells that, given more time, would have otherwise finished their normal developmental program.
细胞培养研究已确定肿瘤抑制因子p53是S期检查点控制系统的一个组成部分，而在整个脊椎动物系统中对p53这一作用的体内研究却很有限。在此，我们基于平头（fla）基因的定位克隆，描述了DNA聚合酶δ催化亚基1中的斑马鱼突变体。fla突变体在内脏头部骨骼的晚期增殖区域，如眼睛、大脑和软骨元件中表现出特定缺陷，这些区域的细胞DNA复制受损，随后发生凋亡，受影响组织部分或完全丧失。在fla突变体中，反义介导的p53基因敲低导致所有表型特征显著恢复，包括复制完成、细胞存活以及正常分化和组织形成。这表明在复制受损的条件下，S期检查点的p53分支负责清除停滞的细胞，否则这些细胞在有更多时间的情况下会完成其正常发育程序。
