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

Autor:	Lin X; Institute for Cancer Genetics, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA., Gupta D; New York University School of Medicine, New York, NY 10016, USA., Vaitsiankova A; Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK., Bhandari SK; Cancer Research Facility, Departments of Internal Medicine and Molecular Genetics & Microbiology, University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, 915 Camino de Salud, 1 University of New Mexico, Albuquerque, NM 87131, USA., Leung KSK; Columbia College, Columbia University, New York, NY 10027, USA., Menolfi D; Institute for Cancer Genetics, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA., Lee BJ; Institute for Cancer Genetics, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA., Russell HR; Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Gershik S; Institute for Cancer Genetics, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA., Huang X; Institute for Cancer Genetics, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA., Gu W; Institute for Cancer Genetics, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA; Department of Pathology & Cell Biology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA., McKinnon PJ; Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Dantzer F; Poly(ADP-ribosyl)ation and Genome Integrity, Strasbourg drug discovery and development Institute (IMS), UMR7242, Centre Nationale de la Recherche Scientifique/Université de Strasbourg, Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg, 300 bld. S. Brant, CS10413, 67412 Illkirch, France., Rothenberg E; New York University School of Medicine, New York, NY 10016, USA., Tomkinson AE; Cancer Research Facility, Departments of Internal Medicine and Molecular Genetics & Microbiology, University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, 915 Camino de Salud, 1 University of New Mexico, Albuquerque, NM 87131, USA., Zha S; Institute for Cancer Genetics, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA; Department of Pathology & Cell Biology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA; Department of Pediatrics, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA; Department of Immunology & Microbiology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA. Electronic address: sz2296@cumc.columbia.edu.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2024 Oct 17; Vol. 84 (20), pp. 3916-3931.e7. Date of Electronic Publication: 2024 Oct 08.
DOI:	10.1016/j.molcel.2024.09.020
Abstrakt:	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. Competing Interests: Declaration of interests D.M. is a scientific editor for Molecular Cell and therefore was not involved in the peer review or the decision-making process of this manuscript. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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