A unique role of the DNA fragmentation factor in maintaining genomic stability.
DNA fragmentation is a hallmark of apoptosis (programmed cell death). However, the biological function of apoptotic DNA fragmentation remains unclear. Here, we show that DNA fragmentation factor plays an important role for maintaining genomic stability. Inhibition or loss of the DNA fragmentation factor (DFF)/caspase-activated DNase (CAD), whose nuclease activity is responsible for digesting genomic DNA during apoptosis, led to significant increases in spontaneous or induced gene mutations, gene amplifications, and chromosomal instability in primary mouse cells and transformed human cell lines. The mechanism underlying genetic instability in DFF/CAD-deficient cells, at least in part, involves a small but significant elevation in the survival of cells exposed to ionizing radiation, suggesting that apoptotic DNA fragmentation factor contributes to genomic stability by ensuring the removal of cells that have suffered DNA damage. In support of this hypothesis are the observations of increased cellular transformation of mouse embryonic cells from the DFF/CAD-null mice and significantly enhanced susceptibility to radiation-induced carcinogenesis in these mice. These data, in combination with published reports on the existence of tumor-specific gene mutations/deletions in the DFF/CAD genes in human cancer samples, suggest that apoptotic DNA fragmentation factor is required for the maintenance of genetic stability and may play a role in tumor suppression.
Yan
Bin
B
Departments of Radiation Oncology and Pathology, Duke University Medical Center, Durham, NC 27710, USA.
Wang
Huili
H
Peng
Yuanlin
Y
Hu
Ye
Y
Wang
He
H
Zhang
Xiuwu
X
Chen
Qi
Q
Bedford
Joel S
JS
Dewhirst
Mark W
MW
Li
Chuan-Yuan
CY
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D002875:Chromosomes / Q000528:radiation effects* / Q000648:ultrastructure; D053938:DNA Fragmentation; D003851:Deoxyribonucleases / Q000502:physiology*; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D016678:Genome; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism; D009381:Neoplasms, Radiation-Induced / Q000473:pathology*; D010957:Plasmids / Q000378:metabolism; D013997:Time Factors; D019076:Transgenes
D051017:Apoptosis Regulatory Proteins; C109664:caspase-activated DNase inhibitor; D003851:Deoxyribonucleases; C109663:caspase-activated deoxyribonuclease