Exposure of the human population to cancer-causing substances in the environment constitutes an important hazard to human health. Among these chemicals are polycyclic aromatic hydrocarbons in urban polluted environments and in cigarette smoke, and aromatic amines mutagens present in cooked foods. These chemicals, once they enter the human body, are activated to highly reactive intermediates that chemically bind to DNA, thus generating bulky adducts. The latter, if not removed by cellular defense mechanisms, can cause mutations and cancer. One of the critical lines of defense of the human body to these environmental carcinogens is DNA repair, specifically by the nucleotide excision repair (NER) mechanism that deals with bulky DNA damage. Unfortunately, the molecule basis of this critical defense mechanism, especially its efficiency in removing important, structurally different DNA lesions, is still obscure. In this project, a systematic approach towards solving this problem is proposed that will identify the kind of carcinogen-DNA lesions that are poorly repaired by NER mechanisms. This information will be useful in biomarker studies of environmental human exposure, and will be especially useful for identifying individuals who, because of genetic polymorphisms, are of particular risk of developing cancer. Such individuals can then be selected for closer monitoring to prevent the development of this disease into tits later life-threatening stages. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA099194-06
Application #
7382897
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Okano, Paul
Project Start
2003-01-01
Project End
2012-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
6
Fiscal Year
2008
Total Cost
$326,840
Indirect Cost
Name
New York University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041968306
City
New York
State
NY
Country
United States
Zip Code
10012
Cohen, Isadora S; Bar, Carmit; Paz-Elizur, Tamar et al. (2015) DNA lesion identity drives choice of damage tolerance pathway in murine cell chromosomes. Nucleic Acids Res 43:1637-45
Izhar, Lior; Ziv, Omer; Cohen, Isadora S et al. (2013) Genomic assay reveals tolerance of DNA damage by both translesion DNA synthesis and homology-dependent repair in mammalian cells. Proc Natl Acad Sci U S A 110:E1462-9
Cai, Yuqin; Zheng, Han; Ding, Shuang et al. (2013) Free energy profiles of base flipping in intercalative polycyclic aromatic hydrocarbon-damaged DNA duplexes: energetic and structural relationships to nucleotide excision repair susceptibility. Chem Res Toxicol 26:1115-25
Kropachev, Konstantin; Kolbanovskiy, Marina; Liu, Zhi et al. (2013) Adenine-DNA adducts derived from the highly tumorigenic Dibenzo[a,l]pyrene are resistant to nucleotide excision repair while guanine adducts are not. Chem Res Toxicol 26:783-93
Minero, Antonio S; Lukashevich, Olga V; Cherepanova, Natalia A et al. (2012) Probing murine methyltransfease Dnmt3a interactions with benzo[a]pyrene-modified DNA by fluorescence methods. FEBS J 279:3965-80
Skosareva, Lidia V; Lebedeva, Natalia A; Rechkunova, Nadejda I et al. (2012) Human DNA polymerase ? catalyzes lesion bypass across benzo[a]pyrene-derived DNA adduct during base excision repair. DNA Repair (Amst) 11:367-73
Tang, Yijin; Liu, Zhi; Ding, Shuang et al. (2012) Nuclear magnetic resonance solution structure of an N(2)-guanine DNA adduct derived from the potent tumorigen dibenzo[a,l]pyrene: intercalation from the minor groove with ruptured Watson-Crick base pairing. Biochemistry 51:9751-62
Cai, Yuqin; Geacintov, Nicholas E; Broyde, Suse (2012) Nucleotide excision repair efficiencies of bulky carcinogen-DNA adducts are governed by a balance between stabilizing and destabilizing interactions. Biochemistry 51:1486-99
Diamant, Noam; Hendel, Ayal; Vered, Ilan et al. (2012) DNA damage bypass operates in the S and G2 phases of the cell cycle and exhibits differential mutagenicity. Nucleic Acids Res 40:170-80
Mu, Hong; Kropachev, Konstantin; Wang, Lihua et al. (2012) Nucleotide excision repair of 2-acetylaminofluorene- and 2-aminofluorene-(C8)-guanine adducts: molecular dynamics simulations elucidate how lesion structure and base sequence context impact repair efficiencies. Nucleic Acids Res 40:9675-90

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