H. Henry Guo

Journal Articles

• Demonstration of peripheral nerve root involvement by non-Hodgkin's lymphoma on F-18-FDG PET/CT EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING Guo, H., Mosci, C., Iagaru, A. 2012; 39 (4): 729-730

  View details for DOI 10.1007/s00259-011-2000-0

  View details for Web of Science ID 000302287500024

  View details for PubMedID 22124779

• Frameshift Mutagenesis and Microsatellite Instability Induced by Human Alkyladenine DNA Glycosylase MOLECULAR CELL Klapacz, J., Lingaraju, G. M., Guo, H. H., Shah, D., Moar-Shoshani, A., Loeb, L. A., Samson, L. D. 2010; 37 (6): 843-853

  Abstract

  Human alkyladenine DNA glycosylase (hAAG) excises alkylated purines, hypoxanthine, and etheno bases from DNA to form abasic (AP) sites. Surprisingly, elevated expression of hAAG increases spontaneous frameshift mutagenesis. By random mutagenesis of eight active site residues, we isolated hAAG-Y127I/H136L double mutant that induces even higher rates of frameshift mutation than does the wild-type hAAG; the Y127I mutation accounts for the majority of the hAAG-Y127I/H136L-induced mutator phenotype. The hAAG-Y127I/H136L and hAAG-Y127I mutants increased the rate of spontaneous frameshifts by up to 120-fold in S. cerevisiae and also induced high rates of microsatellite instability (MSI) in human cells. hAAG and its mutants bind DNA containing one and two base-pair loops with significant affinity, thus shielding them from mismatch repair; the strength of such binding correlates with their ability to induce the mutator phenotype. This study provides important insights into the mechanism of hAAG-induced genomic instability.

  View details for DOI 10.1016/j.molcel.2010.01.038

  View details for Web of Science ID 000276135100011

  View details for PubMedID 20347426

• Best Cases from the AFIP Fatal 2009 Influenza A (H1N1) Infection, Complicated by Acute Respiratory Distress Syndrome and Pulmonary Interstitial Emphysema RADIOGRAPHICS Guo, H. H., Sweeney, R. T., Regula, D., Leung, A. N. 2010; 30 (2): 327-333

  View details for DOI 10.1148/rg.302095213

  View details for Web of Science ID 000275622400003

  View details for PubMedID 20068001

• Substrate binding pocket residues of human alkyladenine-DNA glycosylase critical for methylating agent survival DNA REPAIR Chen, C., Guo, H. H., Shah, D., Blank, A., Samson, L. D., Loeb, L. A. 2008; 7 (10): 1731-1745

  Abstract

  Human alkyladenine-DNA glycosylase (AAG) initiates base excision repair (BER) of alkylated and deaminated bases in DNA. Here, we assessed the mutability of the AAG substrate binding pocket, and the essentiality of individual binding pocket amino acids for survival of methylation damage. We used oligonucleotide-directed mutagenesis to randomize 19 amino acids, 8 of which interact with substrate bases, and created more than 4.5 million variants. We expressed the mutant AAGs in repair-deficient Escherichia coli and selected for protection against the cytotoxicity of either methylmethane sulfonate (MMS) or methyl-lexitropsin (Me-lex), an agent that produces 3-methyladenine as the predominant base lesion. Sequence analysis of 116 methylation-resistant mutants revealed no substitutions for highly conserved Tyr(127)and His(136). In contrast, one mutation, L180F, was greatly enriched in both the MMS- and Me-lex-resistant libraries. Expression of the L180F single mutant conferred 4.4-fold enhanced survival at the high dose of MMS used for selection. The homogeneous L180F mutant enzyme exhibited 2.2-fold reduced excision of 3-methyladenine and 7.3-fold reduced excision of 7-methylguanine from methylated calf thymus DNA. Decreased excision of methylated bases by the mutant glycosylase could promote survival at high MMS concentrations, where the capacity of downstream enzymes to process toxic BER intermediates may be saturated. The mutant also displayed 6.6- and 3.0-fold reduced excision of 1,N(6)-ethenoadenine and hypoxanthine from oligonucleotide substrates, respectively, and a 1.7-fold increase in binding to abasic site-containing DNA. Our work provides in vivo evidence for the substrate binding mechanism deduced from crystal structures, illuminates the function of Leu(180) in wild-type human AAG, and is consistent with a role for balanced expression of BER enzymes in damage survival.

  View details for DOI 10.1016/j.dnarep.2008.06.019

  View details for Web of Science ID 000260621500012

  View details for PubMedID 18706524

• Protein tolerance to random amino acid change PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA GUO, H. H., Choe, J., Loeb, L. A. 2004; 101 (25): 9205-9210

  Abstract

  Mutagenesis of protein-encoding sequences occurs ubiquitously; it enables evolution, accumulates during aging, and is associated with disease. Many biotechnological methods exploit random mutations to evolve novel proteins. To quantitate protein tolerance to random change, it is vital to understand the probability that a random amino acid replacement will lead to a protein's functional inactivation. We define this probability as the "x factor." Here, we develop a broadly applicable approach to calculate x factors and demonstrate this method using the human DNA repair enzyme 3-methyladenine DNA glycosylase (AAG). Three gene-wide mutagenesis libraries were created, each with 10(5) diversity and averaging 2.2, 4.6, and 6.2 random amino acid changes per mutant. After determining the percentage of functional mutants in each library using high-stringency selection (>19,000-fold), the x factor was found to be 34% +/- 6%. Remarkably, reanalysis of data from studies of diverse proteins reveals similar inactivation probabilities. To delineate the nature of tolerated amino acid substitutions, we sequenced 244 surviving AAG mutants. The 920 tolerated substitutions were characterized by substitutability index and mapped onto the AAG primary, secondary, and known tertiary structures. Evolutionarily conserved residues show low substitutability indices. In AAG, beta strands are on average less substitutable than alpha helices; and surface loops that are not involved in DNA binding are the most substitutable. Our results are relevant to such diverse topics as applied molecular evolution, the rate of introduction of deleterious alleles into genomes in evolutionary history, and organisms' tolerance of mutational burden.

  View details for DOI 10.1073/pnas.0403255101

  View details for Web of Science ID 000222278600009

  View details for PubMedID 15197260

• Tumbling down a different pathway to genetic instability JOURNAL OF CLINICAL INVESTIGATION GUO, H. H., Loeb, L. A. 2003; 112 (12): 1793-1795

  Abstract

  Ulcerative colitis (UC), a chronic inflammatory condition associated with a predisposition to colon cancer, is frequently characterized by DNA damage in the form of microsatellite instability (MSI). A new report links inflammation in UC with increases in the DNA repair enzymes 3-methyladenine DNA glycosylase and apurinic/apyrimidinic endonuclease, and, paradoxically, with increased MSI. These findings may represent a novel mechanism contributing to MSI in chronic inflammation.

  View details for DOI 10.1172/JCI200320502

  View details for Web of Science ID 000187348300006

  View details for PubMedID 14679175