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

Fiche publication

Date publication

octobre 2024

Journal

Molecular cell

Auteurs

Membres identifiés du Cancéropôle Est :
Dr DANTZER Françoise

Tous les auteurs :
Lin X, Gupta D, Vaitsiankova A, Bhandari SK, Leung KSK, Menolfi D, Lee BJ, Russell HR, Gershik S, Huang X, Gu W, McKinnon PJ, Dantzer F, Rothenberg E, Tomkinson AE, Zha S

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/39383878

Résumé

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) 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.