Zinkel Sandra S, Hurov Kristen E, Ong Christy, Abtahi Farvardean M, Gross Atan, Korsmeyer Stanley J
Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cell. 2005 Aug 26;122(4):579-91. doi: 10.1016/j.cell.2005.06.022.
The BCL-2 family of apoptotic proteins encompasses key regulators proximal to irreversible cell damage. The BH3-only members of this family act as sentinels, interconnecting specific death signals to the core apoptotic pathway. Our previous data demonstrated a role for BH3-only BID in maintaining myeloid homeostasis and suppressing leukemogenesis. In the absence of Bid, mice accumulate chromosomal aberrations and develop a fatal myeloproliferative disorder resembling chronic myelomonocytic leukemia. Here, we describe a role for BID in preserving genomic integrity that places BID at an early point in the path to determine the fate of a cell. We show that BID plays an unexpected role in the intra-S phase checkpoint downstream of DNA damage distinct from its proapoptotic function. We further demonstrate that this role is mediated through BID phosphorylation by the DNA-damage kinase ATM. These results establish a link between proapoptotic Bid and the DNA-damage response.
凋亡蛋白的BCL-2家族包含紧邻不可逆细胞损伤的关键调节因子。该家族中仅含BH3结构域的成员充当哨兵，将特定的死亡信号与核心凋亡途径相互连接。我们之前的数据表明，仅含BH3结构域的BID在维持髓系稳态和抑制白血病发生中发挥作用。在缺乏Bid的情况下，小鼠会积累染色体畸变，并发展出一种类似于慢性粒单核细胞白血病的致命骨髓增殖性疾病。在此，我们描述了BID在维持基因组完整性中的作用，这使得BID处于决定细胞命运途径的早期阶段。我们表明，BID在DNA损伤下游的S期内检查点中发挥了意想不到的作用，这与其促凋亡功能不同。我们进一步证明，这一作用是由DNA损伤激酶ATM对BID的磷酸化介导的。这些结果在促凋亡的Bid与DNA损伤反应之间建立了联系。
