Abstract
Unlike normal tissues, tumor cells possess a propensity for genomic instability, resulting from elevated oxidant levels produced by oncogenic signaling and aberrant cellular metabolism. Thus, targeting mechanisms that protect cancer cells from the tumor-inhibitory consequences of their redox imbalance and spontaneous DNA-damaging events is expected to have broad-spectrum efficacy and a high therapeutic index. One critical mechanism for tumor cell protection from oxidant stress is the hydrolysis of oxidized nucleotides. Human MutT homolog 1 (MTH1), the mammalian nudix (nucleoside diphosphate X) pyrophosphorylase (NUDT1), protects tumor cells from oxidative stress-induced genomic DNA damage by cleansing the nucleotide pool of oxidized purine nucleotides. Depletion or pharmacologic inhibition of MTH1 results in genomic DNA strand breaks in many cancer cells. However, the mechanisms underlying how oxidized nucleotides, thought mainly to be mutagenic rather than genotoxic, induce DNA strand breaks are largely unknown. Given the recent therapeutic interest in targeting MTH1, a better understanding of such mechanisms is crucial to its successful translation into the clinic and in identifying the molecular contexts under which its inhibition is likely to be beneficial. Here we provide a comprehensive perspective on MTH1 function and its importance in protecting genome integrity, in the context of tumor-associated oxidative stress and the mechanisms that likely lead to irreparable DNA strand breaks as a result of MTH1 inhibition.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 18-26 |
| Number of pages | 9 |
| Journal | DNA Repair |
| Volume | 77 |
| DOIs | |
| State | Published - May 1 2019 |
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Keywords
- 8-oxoguanine
- Cancer
- DNA repair
- DNA strand breaks
- MTH1
- Reactive oxygen species (ROS)
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology
Cite this
Mechanisms of MTH1 inhibition-induced DNA strand breaks : The slippery slope from the oxidized nucleotide pool to genotoxic damage. / Rai, Priyamvada; Sobol, Robert W.
In: DNA Repair, Vol. 77, 01.05.2019, p. 18-26.Research output: Contribution to journal › Review article
}
TY - JOUR
T1 - Mechanisms of MTH1 inhibition-induced DNA strand breaks
T2 - The slippery slope from the oxidized nucleotide pool to genotoxic damage
AU - Rai, Priyamvada
AU - Sobol, Robert W.
PY - 2019/5/1
Y1 - 2019/5/1
N2 - Unlike normal tissues, tumor cells possess a propensity for genomic instability, resulting from elevated oxidant levels produced by oncogenic signaling and aberrant cellular metabolism. Thus, targeting mechanisms that protect cancer cells from the tumor-inhibitory consequences of their redox imbalance and spontaneous DNA-damaging events is expected to have broad-spectrum efficacy and a high therapeutic index. One critical mechanism for tumor cell protection from oxidant stress is the hydrolysis of oxidized nucleotides. Human MutT homolog 1 (MTH1), the mammalian nudix (nucleoside diphosphate X) pyrophosphorylase (NUDT1), protects tumor cells from oxidative stress-induced genomic DNA damage by cleansing the nucleotide pool of oxidized purine nucleotides. Depletion or pharmacologic inhibition of MTH1 results in genomic DNA strand breaks in many cancer cells. However, the mechanisms underlying how oxidized nucleotides, thought mainly to be mutagenic rather than genotoxic, induce DNA strand breaks are largely unknown. Given the recent therapeutic interest in targeting MTH1, a better understanding of such mechanisms is crucial to its successful translation into the clinic and in identifying the molecular contexts under which its inhibition is likely to be beneficial. Here we provide a comprehensive perspective on MTH1 function and its importance in protecting genome integrity, in the context of tumor-associated oxidative stress and the mechanisms that likely lead to irreparable DNA strand breaks as a result of MTH1 inhibition.
AB - Unlike normal tissues, tumor cells possess a propensity for genomic instability, resulting from elevated oxidant levels produced by oncogenic signaling and aberrant cellular metabolism. Thus, targeting mechanisms that protect cancer cells from the tumor-inhibitory consequences of their redox imbalance and spontaneous DNA-damaging events is expected to have broad-spectrum efficacy and a high therapeutic index. One critical mechanism for tumor cell protection from oxidant stress is the hydrolysis of oxidized nucleotides. Human MutT homolog 1 (MTH1), the mammalian nudix (nucleoside diphosphate X) pyrophosphorylase (NUDT1), protects tumor cells from oxidative stress-induced genomic DNA damage by cleansing the nucleotide pool of oxidized purine nucleotides. Depletion or pharmacologic inhibition of MTH1 results in genomic DNA strand breaks in many cancer cells. However, the mechanisms underlying how oxidized nucleotides, thought mainly to be mutagenic rather than genotoxic, induce DNA strand breaks are largely unknown. Given the recent therapeutic interest in targeting MTH1, a better understanding of such mechanisms is crucial to its successful translation into the clinic and in identifying the molecular contexts under which its inhibition is likely to be beneficial. Here we provide a comprehensive perspective on MTH1 function and its importance in protecting genome integrity, in the context of tumor-associated oxidative stress and the mechanisms that likely lead to irreparable DNA strand breaks as a result of MTH1 inhibition.
KW - 8-oxoguanine
KW - Cancer
KW - DNA repair
KW - DNA strand breaks
KW - MTH1
KW - Reactive oxygen species (ROS)
UR - http://www.scopus.com/inward/record.url?scp=85062392946&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062392946&partnerID=8YFLogxK
U2 - 10.1016/j.dnarep.2019.03.001
DO - 10.1016/j.dnarep.2019.03.001
M3 - Review article
C2 - 30852368
AN - SCOPUS:85062392946
VL - 77
SP - 18
EP - 26
JO - DNA Repair
JF - DNA Repair
SN - 1568-7864
ER -