Deoxyinosine triphosphate induces MLH1/PMS2- and p53-dependent cell growth arrest and DNA instability in mammalian cells.
Deoxyinosine (dI) occurs in DNA either by oxidative deamination of a previously incorporated deoxyadenosine residue or by misincorporation of deoxyinosine triphosphate (dITP) from the nucleotide pool during replication. To exclude dITP from the pool, mammals possess specific hydrolysing enzymes, such as inosine triphosphatase (ITPA). Previous studies have shown that deficiency in ITPA results in cell growth suppression and DNA instability. To explore the mechanisms of these phenotypes, we analysed ITPA-deficient human and mouse cells. We found that both growth suppression and accumulation of single-strand breaks in nuclear DNA of ITPA-deficient cells depended on MLH1/PMS2. The cell growth suppression of ITPA-deficient cells also depended on p53, but not on MPG, ENDOV or MSH2. ITPA deficiency significantly increased the levels of p53 protein and p21 mRNA/protein, a well-known target of p53, in an MLH1-dependent manner. Furthermore, MLH1 may also contribute to cell growth arrest by increasing the basal level of p53 activity.
Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8581, Japan.|Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8581, Japan.
Yasuto
Y
Yoneshima
Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8581, Japan.
Nona
N
Abolhassani
Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8581, Japan.
Teruaki
T
Iyama
Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8581, Japan.|Research Center for Nucleotide Pool, Kyushu University, Fukuoka 812-8581, Japan.
Kunihiko
K
Sakumi
National Institute of Radiological Sciences, Chiba 263-8555, Japan.
Naoko
N
Shiomi
National Institute of Radiological Sciences, Chiba 263-8555, Japan.
Masahiko
M
Mori
National Institute of Radiological Sciences, Chiba 263-8555, Japan.
Tadahiro
T
Shiomi
Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
Tetsuo
T
Noda
Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8581, Japan.|Research Center for Nucleotide Pool, Kyushu University, Fukuoka 812-8581, Japan.
Daisuke
D
Tsuchimoto
Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8581, Japan.|Research Center for Nucleotide Pool, Kyushu University, Fukuoka 812-8581, Japan.
Yusaku
Y
Nakabeppu
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D042822:Genomic Instability / Q000235:genetics*; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D007288:Inosine / Q000032:analysis / Q000378:metabolism*; D007292:Inosine Nucleotides / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000070976:Mismatch Repair Endonuclease PMS2 / Q000378:metabolism*; D000070957:MutL Protein Homolog 1 / Q000378:metabolism*; D011755:Pyrophosphatases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000097630:Inosine Triphosphatase
D050759:Cyclin-Dependent Kinase Inhibitor p21; D004247:DNA; D007288:Inosine; D007292:Inosine Nucleotides; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D011755:Pyrophosphatases; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C493956:CDKN1A protein, human; C501486:MLH1 protein, human; C495901:TP53 protein, human; C523314:Nudt16 protein, human; C094934:PMS2 protein, human; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase; C556621:Itpa protein, mouse