PLA2R1 promotes DNA damage and inhibits spontaneous tumor formation during aging.
Age Factors
Aging
/ genetics
Animals
Cell Line
Cell Proliferation
Cellular Senescence
DNA Damage
Databases, Genetic
Female
Male
Mice, Inbred C57BL
Mice, Knockout
Neoplasms
/ genetics
Poly (ADP-Ribose) Polymerase-1
/ genetics
Reactive Oxygen Species
/ metabolism
Receptors, Phospholipase A2
/ genetics
Retinoblastoma Protein
/ genetics
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
16 02 2021
16 02 2021
Historique:
received:
24
03
2020
accepted:
21
01
2021
revised:
16
01
2021
entrez:
17
2
2021
pubmed:
18
2
2021
medline:
15
9
2021
Statut:
epublish
Résumé
Although aging is a major risk factor for most types of cancers, it is barely studied in this context. The transmembrane protein PLA2R1 (phospholipase A2 receptor) promotes cellular senescence, which can inhibit oncogene-induced tumor initiation. Functions and mechanisms of action of PLA2R1 during aging are largely unknown. In this study, we observed that old Pla2r1 knockout mice were more prone to spontaneously develop a wide spectrum of tumors compared to control littermates. Consistently, these knockout mice displayed increased Parp1, a master regulator of DNA damage repair, and decreased DNA damage, correlating with large human dataset analysis. Forced PLA2R1 expression in normal human cells decreased PARP1 expression, induced DNA damage and subsequent senescence, while the constitutive expression of PARP1 rescued cells from these PLA2R1-induced effects. Mechanistically, PARP1 expression is repressed by a ROS (reactive oxygen species)-Rb-dependent mechanism upon PLA2R1 expression. In conclusion, our results suggest that PLA2R1 suppresses aging-induced tumors by repressing PARP1, via a ROS-Rb signaling axis, and inducing DNA damage and its tumor suppressive responses.
Identifiants
pubmed: 33594040
doi: 10.1038/s41419-021-03468-3
pii: 10.1038/s41419-021-03468-3
pmc: PMC7887270
doi:
Substances chimiques
PLA2R1 protein, human
0
Pla2r1 protein, mouse
0
Reactive Oxygen Species
0
Receptors, Phospholipase A2
0
Retinoblastoma Protein
0
PARP1 protein, human
EC 2.4.2.30
Parp1 protein, mouse
EC 2.4.2.30
Poly (ADP-Ribose) Polymerase-1
EC 2.4.2.30
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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