Repair of Alkylation Damage in Eukaryotic Chromatin Depends on Searching Ability of Alkyladenine DNA Glycosylase

ACS Chemical Biology
Yaru Zhang, Patrick J O'Brien

Abstract

Human alkyladenine DNA glycosylase (AAG) initiates the base excision repair pathway by excising alkylated and deaminated purine lesions. In vitro biochemical experiments demonstrate that AAG uses facilitated diffusion to efficiently search DNA to find rare sites of damage and suggest that electrostatic interactions are critical to the searching process. However, it remains an open question whether DNA searching limits the rate of DNA repair in vivo. We constructed AAG mutants with altered searching ability and measured their ability to protect yeast from alkylation damage in order to address this question. Each of the conserved arginine and lysine residues that are near the DNA binding interface were mutated, and the functional impacts were evaluated using kinetic and thermodynamic analysis. These mutations do not perturb catalysis of N-glycosidic bond cleavage, but they decrease the ability to capture rare lesion sites. Nonspecific and specific DNA binding properties are closely correlated, suggesting that the electrostatic interactions observed in the specific recognition complex are similarly important for DNA searching complexes. The ability of the mutant proteins to complement repair-deficient yeast cells is positively cor...Continue Reading

References

Oct 15, 1992·Proceedings of the National Academy of Sciences of the United States of America·B SingerB Rydberg
Mar 1, 1969·Biophysical Journal·W Veatch, S Okada
Jun 21, 1994·Proceedings of the National Academy of Sciences of the United States of America·M Saparbaev, J Laval
Dec 11, 1993·Nucleic Acids Research·T R O'Connor
Dec 16, 1997·Proceedings of the National Academy of Sciences of the United States of America·B HangR H Elder
Dec 16, 1997·Proceedings of the National Academy of Sciences of the United States of America·B P EngelwardL D Samson
Aug 26, 1998·Proceedings of the National Academy of Sciences of the United States of America·B J GlassnerL D Samson
Nov 30, 2000·Molecular and Cellular Biology·R HaraA Sancar
Dec 6, 2000·Proceedings of the National Academy of Sciences of the United States of America·A Y LauT Ellenberger
Dec 18, 2001·Environmental and Molecular Mutagenesis·V A BespalovM J Smerdon
Jun 12, 2003·Proceedings of the National Academy of Sciences of the United States of America·Brian C BeardMichael J Smerdon
Dec 23, 2003·The Journal of Biological Chemistry·Patrick J O'Brien, Tom Ellenberger
Jun 5, 2004·Nucleic Acids Research·Stephen E Halford, John F Marko
Jun 16, 2004·Proceedings of the National Academy of Sciences of the United States of America·Haiwei H GuoLawrence A Loeb
Jul 13, 2004·The Journal of Biological Chemistry·Thomas M HitchcockWeiguo Cao
Jul 17, 2004·Science·Charalampos G KalodimosRobert Kaptein
Jun 17, 2006·The EMBO Journal·Andrea BucceriFritz Thoma
Oct 9, 2008·Biochemistry·Mark Hedglin, Patrick J O'Brien
Mar 6, 2010·ACS Chemical Biology·Mark Hedglin, Patrick J O'Brien
Aug 13, 2010·Biochemistry·Michael R Baldwin, Patrick J O'Brien
Nov 10, 2011·Molecular Systems Biology·Martin BeckRuedi Aebersold
Oct 18, 2012·Nucleic Acids Research·Michael R Baldwin, Patrick J O'Brien
Jul 11, 2013·The Journal of Biological Chemistry·Mark HedglinPatrick J O'Brien
Oct 18, 2014·Nucleic Acids Research·Jenna M Hendershot, Patrick J O'Brien
Jan 27, 2015·PloS One·Neel S MadhukarJason W Locasale

❮ Previous
Next ❯

Citations

Nov 28, 2015·The FEBS Journal·Carlos H Trasviña-ArenasLuis G Brieba
Mar 24, 2017·PloS One·Daniel E EylerPatrick J O'Brien
Sep 13, 2017·The Journal of Biological Chemistry·Michael J Howard, Samuel H Wilson
Aug 21, 2020·Proceedings of the National Academy of Sciences of the United States of America·Sijia PengChunlai Chen
Nov 1, 2018·Chemical Reviews·Alexandre Esadze, James T Stivers
Oct 29, 2020·Chemical Research in Toxicology·Katelyn L Rioux, Sarah Delaney
Aug 9, 2017·ACS Chemical Biology·Gaddiel RodriguezJames T Stivers
Jun 26, 2018·Biochemistry·Erin L TaylorPatrick J O'Brien

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.