Mechanism of error-free DNA synthesis across N1-methyl-deoxyadenosine by human DNA polymerase-ι

Jain, Rinku; Choudhury, Jayati Roy; Buku, Angeliki; Johnson, Robert E.; Prakash, Louise; Prakash, Satya; Aggarwal, Aneel K.

doi:10.1038/srep43904

Mechanism of error-free DNA synthesis across N1-methyl-deoxyadenosine by human DNA polymerase-ι

Journal Article · Wed Mar 08 04:00:00 EST 2017 · Scientific Reports

DOI:https://doi.org/10.1038/srep43904· OSTI ID:1409564

Jain, Rinku; Choudhury, Jayati Roy; Buku, Angeliki; Johnson, Robert E.; Prakash, Louise; Prakash, Satya; Aggarwal, Aneel K.

N1-methyl-deoxyadenosine (1-MeA) is formed by methylation of deoxyadenosine at the N1 atom. 1-MeA presents a block to replicative DNA polymerases due to its inability to participate in Watson-Crick (W-C) base pairing. Here we determine how human DNA polymerase-ι (Polι) promotes error-free replication across 1-MeA. Steady state kinetic analyses indicate that Polι is ~100 fold more efficient in incorporating the correct nucleotide T versus the incorrect nucleotide C opposite 1-MeA. To understand the basis of this selectivity, we determined ternary structures of Polι bound to template 1-MeA and incoming dTTP or dCTP. In both structures, template 1-MeA rotates to the syn conformation but pairs differently with dTTP versus dCTP. Thus, whereas dTTP partakes in stable Hoogsteen base pairing with 1-MeA, dCTP fails to gain a “foothold” and is largely disordered. Together, our kinetic and structural studies show how Polι maintains discrimination between correct and incorrect incoming nucleotide opposite 1-MeA in preserving genome integrity.

Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

DOE Contract Number:: SC0012704

OSTI ID:: 1409564

Report Number(s):: BNL--114616-2017-JA¿¿¿

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Vol. 7; ISSN 2045-2322

Publisher:: Nature Publishing Group

Country of Publication:: United States

Language:: English

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Infrared Spectroscopic Observation of a G–C ⁺ Hoogsteen Base Pair in the DNA:TATA‐Box Binding Protein Complex Under Solution Conditions Stelling, Allison L.; Liu, Amy Y.; Zeng, Wenjie Angewandte Chemie, Vol. 131, Issue 35 https://doi.org/10.1002/ange.201902693	journal	July 2019
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