Inactive Parp2 causes Tp53-dependent lethal anemia by blocking replication-associated nick ligation in erythroblasts

• DOI: 10.1016/j.molcel.2024.09.020
• Publication Date: 2024-10-08T14:38:41Z
• Authors: Xiaohui Lin; Dipika Gupta; Alina Vaitsiankova; Seema Khattri Bha...; Kay Sze Karina Leung; Demis Menolfi; Brian J. Lee; Helen R. Russell; Steven Gershik; Xiaoyu Huang; Wei Gu; Peter J. McKinnon; Françoise Dantzer; Eli Rothenberg; Alan E. Tomkinson; Shan Zha

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.