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

Xiaohui Lin, Dipika Gupta, Alina Vaitsiankova

    Biorxiv : the Preprint Server for Biology
    |April 1, 2024
    PubMed

    Insights

    Poly (ADP-ribose) polymerase inhibitors (PARPi) cause anemia by trapping inactive PARP2 at DNA replication sites, hindering DNA repair in erythroblasts. This reveals the mechanism behind PARPi-induced hematological toxicities.

    Area of Science:

    • Molecular Biology
    • Cancer Biology
    • Genetics

    Background:

    • Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective cancer therapies but cause severe anemia and leukemia.
    • The exact mechanisms behind these PARPi-induced hematological toxicities remain unclear.
    • PARP inhibitors are known to inhibit enzymatic activity and trap PARP1/2 at DNA lesions.

    Approach:

    • Investigated the role of PARP2 in erythropoiesis using catalytically inactive Parp2 mutant mice (E534A).
    • Analyzed the recruitment and activation of PARP2 at 5'-phosphorylated nicks during DNA replication, particularly in relation to Okazaki fragment ligation.
    • Examined the impact of inactive PARP2 on DNA ligase activity and replication fork stability in erythroblasts.

    Key Points:

    • Catalytically inactive PARP2 (E534A), but not its absence or active form, causes severe erythropoietic failure dependent on Tp53 and Chk2.
    • PARP2 is robustly activated by DNA replication and selectively recruited to 5'-phosphorylated nicks, sites typically resolved by Lig1.
    • Inactive PARP2 impedes Lig1 and Lig3-mediated ligation, leading to replication fork collapse, especially in erythroblasts with rapid replication forks.

    Conclusions:

    • The hematological toxicities of PARPi are caused by the presence of inactive PARP2 protein, not impaired enzymatic activity.
    • Inactive PARP2 interferes with DNA ligation at Okazaki fragments, causing replication stress and cell death in erythroblasts.
    • This study elucidates the mechanism of PARPi-induced anemia and leukemia, particularly in contexts of TP53/CHK2 loss.

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