Deoxyribonuclease I is essential for DNA fragmentation induced by gamma radiation in mice.
Gamma radiation is known to induce cell death in several organs. This damage is associated with endonuclease-mediated DNA fragmentation; however, the enzyme that produces the latter and is likely to cause cell death is unknown. To determine whether the most abundant cytotoxic endonuclease DNase I mediates gamma-radiation-induced tissue injury, we used DNase I knockout mice and zinc chelate of 3,5-diisopropylsalicylic acid (Zn-DIPS), which, as we show, has DNase I inhibiting activity in vitro. The study demonstrated for the first time that inactivation or inhibition of DNase I ameliorates radiation injury to the white pulp of spleen, intestine villi and bone marrow as measured using a quantitative TUNEL assay. The spleen and intestine of DNase I knockout mice were additionally protected from radiation by Zn-DIPS, perhaps due to the broad radioprotective effect of the zinc ions. Surprisingly, the main DNase I-producing tissues such as the salivary glands, pancreas and kidney showed no effect of DNase I inactivation. Another unexpected observation was that even without irradiation, DNA fragmentation and cell death were significantly lower in the intestine of DNase I knockout mice than in wild-type mice. This points to the physiological role of DNase I in normal cell death in the intestinal epithelium. In conclusion, our results suggested that DNase I-mediated mechanism of DNA damage and subsequent tissue injury are essential in gamma-radiation-induced cell death in radiosensitive organs.
Apostolov
Eugene O
EO
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Soultanova
Izoumroud
I
Savenka
Alena
A
Bagandov
Osman O
OO
Yin
Xiaoyan
X
Stewart
Anna G
AG
Walker
Richard B
RB
Basnakian
Alexei G
AG
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000293:injuries / Q000473:pathology / Q000528:radiation effects; D002614:Chelating Agents / Q000737:chemistry; D053938:DNA Fragmentation / Q000187:drug effects / Q000528:radiation effects*; D003850:Deoxyribonuclease I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005720:Gamma Rays / Q000009:adverse effects*; D055786:Gene Knockout Techniques; D007082:Ileum / Q000187:drug effects / Q000293:injuries / Q000473:pathology / Q000528:radiation effects; D007583:Jejunum / Q000187:drug effects / Q000293:injuries / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D011833:Radiation Injuries, Experimental / Q000473:pathology; D051381:Rats; D012459:Salicylates / Q000737:chemistry / Q000494:pharmacology; D013154:Spleen / Q000187:drug effects / Q000293:injuries / Q000473:pathology / Q000528:radiation effects; D016019:Survival Analysis; D014916:Whole-Body Irradiation / Q000009:adverse effects; D015032:Zinc / Q000737:chemistry
D002614:Chelating Agents; D004791:Enzyme Inhibitors; D012459:Salicylates; C067227:3,5-diisopropylsalicylic acid; D003850:Deoxyribonuclease I; D015032:Zinc