Deoxyinosine triphosphate induces MLH1/PMS2- and p53-dependent cell growth arrest and DNA instability in mammalian cells

Yasuto Yoneshima, Nona Abolhassani, Teruaki Iyama, Sakumi Kunihiko, Naoko Shiomi, Masahiko Mori, Tadahiro Shiomi, Tetsuo Noda, Daisuke Tsuchimoto, Yusaku Nakabeppu

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number32849
JournalScientific reports
Volume6
DOIs
Publication statusPublished - Sep 13 2016

Fingerprint

DNA
Growth
Deamination
deoxyinosine
triphosphoric acid
Mammals
Proteins
Nucleotides
Phenotype
Messenger RNA
inosine triphosphatase
Enzymes
Inosine Triphosphatase Deficiency

All Science Journal Classification (ASJC) codes

  • General

Cite this

Deoxyinosine triphosphate induces MLH1/PMS2- and p53-dependent cell growth arrest and DNA instability in mammalian cells. / Yoneshima, Yasuto; Abolhassani, Nona; Iyama, Teruaki; Kunihiko, Sakumi; Shiomi, Naoko; Mori, Masahiko; Shiomi, Tadahiro; Noda, Tetsuo; Tsuchimoto, Daisuke; Nakabeppu, Yusaku.

In: Scientific reports, Vol. 6, 32849, 13.09.2016.

Research output: Contribution to journalArticle

@article{4c61138abdb94fe1aabec2326bb9321f,
title = "Deoxyinosine triphosphate induces MLH1/PMS2- and p53-dependent cell growth arrest and DNA instability in mammalian cells",
abstract = "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.",
author = "Yasuto Yoneshima and Nona Abolhassani and Teruaki Iyama and Sakumi Kunihiko and Naoko Shiomi and Masahiko Mori and Tadahiro Shiomi and Tetsuo Noda and Daisuke Tsuchimoto and Yusaku Nakabeppu",
year = "2016",
month = "9",
day = "13",
doi = "10.1038/srep32849",
language = "English",
volume = "6",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Deoxyinosine triphosphate induces MLH1/PMS2- and p53-dependent cell growth arrest and DNA instability in mammalian cells

AU - Yoneshima, Yasuto

AU - Abolhassani, Nona

AU - Iyama, Teruaki

AU - Kunihiko, Sakumi

AU - Shiomi, Naoko

AU - Mori, Masahiko

AU - Shiomi, Tadahiro

AU - Noda, Tetsuo

AU - Tsuchimoto, Daisuke

AU - Nakabeppu, Yusaku

PY - 2016/9/13

Y1 - 2016/9/13

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84987722698&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84987722698&partnerID=8YFLogxK

U2 - 10.1038/srep32849

DO - 10.1038/srep32849

M3 - Article

C2 - 27618981

AN - SCOPUS:84987722698

VL - 6

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 32849

ER -