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

ABSTRACT: 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 Parp2^EA/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

SUBMITTER: Lin X 

PROVIDER: S-EPMC11615737 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature