聚 (ADP-核糖) 聚合酶 (PARP) 1 和 2 酶抑制剂 (PARPi) 是有前景的癌症治疗方法。但最近，它们的使用受到无法解释的严重贫血和治疗相关白血病的阻碍。除了酶抑制之外，PARPi 还在 DNA 损伤处捕获 PARP1 和 2。在这里，我们报告说，与正常发育的 Parp2-/- 小鼠不同，表达催化失活 Parp2（E534A 和 Parp2EA/EA）的小鼠在子宫内会出现 Tp53 和 Chk2 依赖性红细胞生成衰竭，这与 Lig1-/- 小鼠相似。虽然 DNA 损伤主要激活 PARP1，但我们证明 DNA 复制会强力激活 PARP2。 PARP2 被 5'-磷酸化切口 (5'p-切口) 选择性招募和激活，包括冈崎片段之间的切口，由连接酶 1 (Lig1) 和 Lig3 解析。失活的 PARP2（而非其活性形式或缺失）会阻碍 Lig1 和 Lig3 介导的连接，导致剂量依赖性复制叉塌陷，这对具有超快复制叉的红细胞不利。 PARP2 5'p 缺口处的这种 PARylation 依赖性结构功能解释了 PARP2 失活对红细胞生成的不利影响，揭示了 PARPi 诱导的贫血和 TP53/CHK2 丢失的选择。版权所有 © 2024 Elsevier Inc. 保留所有权利。

Poly (ADP-ribose) polymerase (PARP) 1 and 2 enzymatic inhibitors (PARPi) are promising cancer treatments. But recently, their use has been hindered by unexplained severe anemia and treatment-related leukemia. In addition to enzymatic inhibition, PARPi also trap PARP1 and 2 at DNA lesions. Here we report that, unlike Parp2-/- mice, which develop normally, mice expressing catalytically inactive Parp2 (E534A and Parp2EA/EA) succumb to Tp53- and Chk2-dependent erythropoietic failure in utero, mirroring Lig1-/- mice. While DNA damage mainly activates PARP1, we demonstrate that DNA replication activates PARP2 robustly. PARP2 is selectively recruited and activated by 5'-phosphorylated nicks (5'p-nicks), including those between Okazaki fragments, resolved by ligase 1 (Lig1) and Lig3. Inactive PARP2, but not its active form or absence, impedes Lig1- and Lig3-mediated ligation, causing dose-dependent replication fork collapse, which is detrimental to erythroblasts with ultra-fast forks. This PARylation-dependent structural function of PARP2 at 5'p-nicks explains the detrimental effects of PARP2 inactivation on erythropoiesis, shedding light on PARPi-induced anemia and the selection for TP53/CHK2 loss.Copyright © 2024 Elsevier Inc. All rights reserved.