| First Author | Lin X | Year | 2024 |
| Journal | Mol Cell | Volume | 84 |
| Issue | 20 | Pages | 3916-3931.e7 |
| PubMed ID | 39383878 | Mgi Jnum | J:358182 |
| Mgi Id | MGI:7779492 | Doi | 10.1016/j.molcel.2024.09.020 |
| Citation | Lin X, et al. (2024) Inactive Parp2 causes Tp53-dependent lethal anemia by blocking replication-associated nick ligation in erythroblasts. Mol Cell 84(20):3916-3931.e7 |
| abstractText | 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 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. |
