SPARCLE, a p53-induced lncRNA, controls apoptosis after genotoxic stress by promoting PARP-1 cleavage

  • Mol Cell. 2022 Feb 17;82(4):785-802.e10. doi: 10.1016/j.molcel.2022.01.001.
Karla F Meza-Sosa  1 ,  Rui Miao  2 ,  Francisco Navarro  3 ,  Zhibin Zhang  2 ,  Ying Zhang  2 ,  Jun Jacob Hu  4 ,  Corrine Corrina R Hartford  5 ,  Xiao Ling Li  5 ,  Gustavo Pedraza-Alva  6 ,  Leonor Pérez-Martínez  6 ,  Ashish Lal  5 ,  Hao Wu  4 ,  Judy Lieberman  7
Affiliations
  • 1. Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Laboratorio de Neuroinmunobiología, Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, MOR 62210, México. Electronic address: [email protected].
  • 2. Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
  • 3. Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Bluebird Bio, Cambridge, MA 02142, USA.
  • 4. Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 5. Regulatory RNAs and Cancer Section, Genetics Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20895, USA.
  • 6. Laboratorio de Neuroinmunobiología, Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, MOR 62210, México.
  • 7. Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 35104452 DOI: 10.1016/j.molcel.2022.01.001
Abstract

p53, master transcriptional regulator of the genotoxic stress response, controls cell-cycle arrest and Apoptosis following DNA damage. Here, we identify a p53-induced lncRNA suicidal PARP-1 cleavage enhancer (SPARCLE) adjacent to miR-34b/c required for p53-mediated Apoptosis. SPARCLE is a ∼770-nt, nuclear lncRNA induced 1 day after DNA damage. Despite low expression (<16 copies/cell), SPARCLE deletion increases DNA repair and reduces DNA-damage-induced Apoptosis as much as p53 deficiency, while its overexpression restores Apoptosis in p53-deficient cells. SPARCLE does not alter gene expression. SPARCLE binds to PARP-1 with nanomolar affinity and causes Apoptosis by acting as a Caspase-3 cofactor for PARP-1 cleavage, which separates PARP-1's N-terminal (NT) DNA-binding domain from its catalytic domains. NT-PARP-1 inhibits DNA repair. Expressing NT-PARP-1 in SPARCLE-deficient cells increases unrepaired DNA damage and restores Apoptosis after DNA damage. Thus, SPARCLE enhances p53-induced Apoptosis by promoting PARP-1 cleavage, which interferes with DNA-damage repair.

Keywords
PARP-1; apoptosis; genotoxic stress; lncRNA; miR-34; p53.