Back to Search
Start Over
SPARCLE, a p53-induced lncRNA, controls apoptosis after genotoxic stress by promoting PARP-1 cleavage.
- Source :
-
Molecular cell [Mol Cell] 2022 Feb 17; Vol. 82 (4), pp. 785-802.e10. Date of Electronic Publication: 2022 Jan 31. - Publication Year :
- 2022
-
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.<br />Competing Interests: Declaration of interests The authors declare no competing interests.<br /> (Copyright © 2022. Published by Elsevier Inc.)
- Subjects :
- A549 Cells
Animals
Colorectal Neoplasms genetics
Colorectal Neoplasms pathology
DNA Repair
Gene Expression Regulation, Neoplastic
HCT116 Cells
HEK293 Cells
Hep G2 Cells
Humans
Male
Mice, Nude
MicroRNAs genetics
MicroRNAs metabolism
Poly (ADP-Ribose) Polymerase-1 genetics
RNA, Long Noncoding genetics
Signal Transduction
Tumor Suppressor Protein p53 genetics
Mice
Apoptosis
Caspase 3 metabolism
Colorectal Neoplasms enzymology
DNA Breaks, Double-Stranded
DNA Breaks, Single-Stranded
Poly (ADP-Ribose) Polymerase-1 metabolism
RNA, Long Noncoding metabolism
Tumor Suppressor Protein p53 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4164
- Volume :
- 82
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular cell
- Publication Type :
- Academic Journal
- Accession number :
- 35104452
- Full Text :
- https://doi.org/10.1016/j.molcel.2022.01.001