The research interests in my laboratory are primarily centered in the field of DNA damage and repair, particularly the identification and repair of novel and/or biologically important DNA adducts, and the implications for exposure biomarkers and disease mechanisms.
Our primary research over twenty years, including the early collaboration with Dr. B. Singer at Berkeley Lab, has been focused on combining chemical, biochemical and biological approaches to understand the key questions in environmental mutagenesis and carcinogenesis. The chemical compounds selected for such purposes all react with DNA to modify bases. One focus of our long-term studies has been on testing new bulky DNA base lesions, particularly the exocyclic DNA adducts that are a group of base modifications with similar chemical structures, for their effects on DNA local structure as well as cellular processes, mainly DNA repair. We have developed in vitro bioassay systems based on chemical synthesis of defined oligonucleotides containing a site-directed adduct. These studies have led to mutagenic/structural characterization of selected adducts and identification of novel substrates/mechanisms for various repair enzymes, which have enhanced our understanding of how adducts would be repaired in vitro (immediate goals) and in vivo (long-term goals) and how repair enzymes would interact with adducted DNA at the molecular level.
One of our new projects is on the genotoxicity of thirdhand smoke (THS), a relatively new type of cigarette hazard that has received public attention since 2009 (New York Times 2009). THS contains residual tobacco smoke compounds that remain on indoor surfaces and in dust after tobacco has been smoked, or are re-emitted back into the gas phase. On top of that, some chemicals react with oxidants and other pollutants in the environment to produce secondary toxicants (Matt et al., EHP, 2011). For example, surface-bound nicotine, a major constituent of THS, can form mutagenic and carcinogenic tobacco-specific nitrosamines (TSNAs) when it reacts with a common indoor pollutant nitrous acid (Sleiman et al., PNAS, 2011). THS may adversely affect human health; a particularly vulnerable population could be small children who may get exposed to THS toxicants through inhalation, ingestion and dermal contact. Our primary task is to investigate cellular and molecular effects of THS and its constituents. We have shown, for the first time, that THS as well as NNA cause DNA strand beaks and oxidative damage in genes (Hang et al., Mutagenesis, 2013). NNA (1-(N-methyl-N-nitrosamino)-1-(3-pyridinyl)-4-butanal) is the major TSNA product identified from THS and is absent in freshly emitted SHS. We are also identifying and charactering new DNA adducts formed by THS compounds. Our goal is to identify and develop novel/unique mechanism-based biomarkers for assessing exposure to THS. This project is supported by the Tobacco-Related Disease Research Program (TRDRP)(CA), through the Consortium of Thirdhand Tobacco Smoke Exposure and Public Health Risk Assessment.
Another research direction my lab is exploring, along with our collaborators, is the involvement of the base excision repair (BER) pathway in epigenetic regulatory mechanisms, specifically the active DNA demethylation in mammalian cells. There still are many unsolved and crucial questions related to this process that could well be linked to pathogenesis of known human diseases. Ultimately we hope to understand how the activity and targeting of relevant BER enzymes are regulated normally and how they become dysfunctional in those “epigenetic diseases” associated with aberrant gene silencing by DNA methylation, such as the Fragile X syndrome and in cancer.
Hang B, Sarker AH, Havel C, Saha S, Hazra TK, Schick S, Jacob P 3rd, Rehan VK, Chenna A, Sharan D, Sleiman M, Destaillats H, Gundel LA. Thirdhand smoke causes DNA damage in human cells. Mutagenesis. 28, 381-91 (2013).
Sarker AH, Chatterjee A, Williams M, Lin S, Havel C, Jacob Iii P, Boldogh I, Hazra TK, Talbot P, Hang B. NEIL2 Protects against Oxidative DNA Damage Induced by sidestream smoke in human cells. PLoS One. Mar 3;9(3):e90261 (2014).
Dey S, Maiti AK, Hegde ML, Hegde PM, Boldogh I, Sarkar PS, Abdel-Rahman SZ, Sarker AH, Hang B, Xie J, Tomkinson AE, Zhou M, Shen B, Wang G, Wu C, Yu D, Lin D, Cardenas V, Hazra TK. Increased risk of lung cancer associated with a functionally impaired polymorphic variant of the human DNA glycosylase NEIL2. DNA Repair (Amst). 11, 570-8 (2012).
Matt, GE, Quintana, PJE, Destaillats, H, Gundel, LA, Mohamad, S, Singer, BC, Jacob III, J, Benowitz, N, Winickoff, JP, Rehan, V, Talbot, P, Schick, S, Samet, J, Wang, Y, Hang, B, Martins-Green, M, and Hovell, MF. Thirdhand tobacco smoke: Emerging evidence and arguments for a multidisciplinary research agenda. Environ Health Perspect. 119, 1218-26 (2012).
Hang, B. Formation and Repair of tobacco carcinogen-derived bulky DNA adducts. J. of Nucleic Acids, Special issue: DNA Damage, Mutagenesis, and DNA Repair, Editors: Basu, A., Broyde, S., Iwai, S., and Kisker, C, Dec. 20 (2010).
Rodriguez, B, Yang, Y, Guliaev, AB, Chenna, A. and Hang, B. Benzene-derived N2-(4-hydroxyphenyl)-deoxyguanosine adduct: UvrABC nuclease incision and its conformation in DNA. Toxicol Lett. 193, 26-32 (2010).
Chenna, A., Gupta, R., Bonala, R., Johnson, F. and Hang, B. Synthesis of the fully protected phosphoramidite of the benzene-DNA adduct, N2-(4-hydroxyphenyl)-2'-doxyguanosine and incorporation of the later into DNA oligomers. Nucleosides, Nucleotides & Nucleic Acids, 27, 979-91 (2008).
Hang, B. and Guliaev, AB. Substrate specificity of human thymine-DNA glycosylase on exocyclic cytosine adducts. Chem Biol Interact., 165, 230-8 (2007).
Wang, P., Guliaev, AB. and Hang, B. Metal inhibition of human N-methylpurine-DNA glycosylase activity in base excision repair. Toxicol Lett., 166, 237-47 (2006).
Xie, Z., Zhang, Y., Guliaev, AB., Shen, H., Hang, B., Singer, B. and Wang, Z. The p-benzoquinone DNA adducts derived from benzene are highly mutagenic. DNA Repair, 8, 1399-409 (2005).
Hang, B. Repair of exocyclic DNA adducts: rings of complexity. BioEssays, 26, 1195-208 (2004).
Guliaev, AB., Singer, B. and Hang, B. Chloroethylnitrosoureas-derived ethano adenine and cytosine adducts are substrates for E. coli glycosylases excising analogous etheno adducts. DNA Repair, 3, 1195-208 (2004).
Guliaev, AB., Hang, B. and Singer, B. Structural insights by molecular dynamics simulations into specificity of the major human AP endonuclease toward the benzene-derived DNA adduct, pBQ-C. Nucleic Acids Res., 32, 2844-52 (2004).
Hang, B., Downing, G., Guliaev, AB. and Singer, B. Novel activity of Escherichia coli mismatch uracil glycosylase (MUG) excising 8-(hydroxymethyl)-3,N4-ethenocytosine, a potential product resulting from glycidaldehyde reaction. Biochemistry, 41, 2158-65 (2002).
Singer, B., Medina, M., Wang, Z., Guliaev, AB. and Hang, B. 8-(hydroxymethyl) 3,N4-etheno-dC, a potential carcinogenic glycidaldehyde product, miscodes in vitro using mammalian polymerases. Biochemistry, 41, 1778-85 (2002).
Singer, B. and Hang, B. Commentary: Nucleic acid sequence and repair: role of adduct, neighbor bases and enzyme specificity. Carcinogenesis, 21, 1071-8 (2000).
Hang, B., Medina, M., Fraenkel-Conrat, H. and Singer, B. A 55-kDa protein isolated from human cells shows DNA glycosylase activity toward 3,N4-ethenocytosine and the G/T mismatch. Proc. Natl. Acad. Sci. USA, 95, 13561-6 (1998).
Hang, B., Singer, B., Margison, GP. and Elder, RH. Targeted deletion of alkylpurine-DNA-N-glycosylase in mice eliminate repair of 1,N6-ethenoadenine and hypoxanthine but not of 3,N4-ethenocytosine or 8-oxoguanine. Proc. Natl. Acad. Sci. USA, 94, 12869-74 (1997).
Singer, B. and Hang, B. Perspective: What structural features determine repair enzyme specificity and mechanism in chemically modified DNA? Chem. Res. Toxicol., 10, 713-32 (1997).
Hang, B., Chenna, A., Fraenkel-Conrat, H. and Singer, B. An unusual mechanism for the major human AP endonuclease involving 5' cleavage of DNA containing a benzene-derived exocyclic adduct in the absence of an AP site. Proc. Natl. Acad. Sci. USA, 93, 13737-41 (1996).
In the News
The Sacramento Bee: Thirdhand smoke poses health danger, especially to children, scientists say (2014.3.19); http://www.sacbee.com/2014/03/18/6248726/thirdhand-smoke-poses-health-danger.html
Medical News Today: Thirdhand smoke "damages DNA and may cause cancer" (2014.3.17); http://www.medicalnewstoday.com/articles/274143.php
Fox News (TV): "Thirdhand" smoke poses cancer risk (2014.3.17); http://www.foxnews.com/health/2014/03/17/thirdhand-smoke-poses-cancer-risk/
CBS News: DNA damage seen from "thirdhand smoke" (2014.3.17); http://www.cbsnews.com/videos/dna-damage-seen-from-thirdhand-smoke/
National Public Radio: Scientists search for toxins in cigarette smoke residue (2014.3.17); http://www.npr.org/blogs/health/2014/03/17/290858487/scientists-search-for-toxins-in-cigarette-smoke-residue
National Geographic: Thirdhand smoke is real - and risky to your health (2014.3.20); http://news.nationalgeographic.com/news/2014/03/140320-thirdhand-smoke-cigarettes-cancer/
American Chemical Society (ACS): Major "third-hand smoke" compound causes DNA damage — and potentially cancer (2014.3.17); http://www.acs.org/content/acs/en/pressroom/newsreleases/2014/march/major-third-hand-smoke-compound-causes-dna-damage-and-potentially-cancer.html
Huffington Post: Thirdhand smoke spurs DNA damage, study finds (2013.6.24); http://www.huffingtonpost.com/2013/06/24/thirdhand-smoke-dna-damage-cells_n_3474797.html
Daily Mail: Pioneering study claims THIRD-HAND smoke causes significant damage to our DNA - and its danger increases over time (2013.6.21); http://www.dailymail.co.uk/sciencetech/article-2345815/Pioneering-study-claims-THIRD-HAND-smoke-causes-significant-genetic-mutations--danger-increases-time.html
Science Daily: Thirdhand smoke causes DNA damage (2013.6.20); http://www.sciencedaily.com/releases/2013/06/130620132459.htm
Lawrence Berkeley National Laboratory: Berkeley Lab confirms thirdhand smoke causes DNA damage (2013.6.20); http://newscenter.lbl.gov/feature-stories/2013/06/20/berkeley-lab-confirms-thirdhand-smoke-causes-dna-damage/