Chronic sub-lethal oxidative stress by spermine oxidase overactivity induces continuous DNA repair and hypersensitivity to radiation exposure.
In the aging process and in most degenerative diseases, the oxidant by-products of cellular metabolism lead to oxidative stress. Oxidative stress plays an important role in switching from cell proliferation to its opposite outcome, cell death. The metabolic pathways in charge of the interconversion and degradation of the polyamines are responsible for oxidant by-products. In the past few years, spermine metabolism has been found closely related to DNA oxidation and apoptosis. Moreover, that the ectopical expression of murine spermine oxidase induced DNA damage in the neuroblastoma cell line, and this was uncoupled with any increase in cell mortality, thus suggests an activation of DNA repair. In this work, we provide new evidence showing that only spermine oxidase overactivity can deliver sub-lethal chronic DNA damage and repair without affecting transcriptional and enzymatic levels of the PA key regulatory enzymes ODC and SSAT. Chronic sub-lethal DNA damage is below the cell cycle arrest induction threshold, but is able to activate apurinic/apyrimidinic endonuclease protein (APE1) and gamma H2AX. Of therapeutic interest, the chronic sub-lethal DNA damage and activation of the repair processes are in turn responsible for inducing hypersensitivity after exposure to radiation with no induction of adaptive response to damage.
Bianchi
M
M
ENEA, ION IRP, CR Casaccia, Via Anguillarese 301, 00060 Roma, Italy.
Bellini
A
A
Cervelli
M
M
Degan
P
P
Marcocci
L
L
Martini
F
F
Scatteia
M
M
Mariottini
P
P
Amendola
R
R
D000375:Aging / Q000378:metabolism / Q000528:radiation effects; D000818:Animals; D016923:Cell Death / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects*; D004249:DNA Damage / Q000235:genetics / Q000528:radiation effects*; D004260:DNA Repair / Q000235:genetics / Q000528:radiation effects*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D051379:Mice; D018384:Oxidative Stress / Q000528:radiation effects*; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000096:biosynthesis* / Q000235:genetics; D014965:X-Rays; D000097667:Polyamine Oxidase
D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D006657:Histones; D000587:Oxidoreductases Acting on CH-NH Group Donors; D000097667:Polyamine Oxidase; C486216:Apex1 protein, mouse; C475961:gamma-H2AX protein, mouse