Mechanism of error-free DNA synthesis across N1-methyl-deoxyadenosine by human DNA polymerase-$\iota$

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-$$\iota$$

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

DOI:https://doi.org/10.1038/srep43904· OSTI ID:1430322

Jain, Rinku ^[1]; Choudhury, Jayati Roy ^[2]; Buku, Angeliki ^[1]; Johnson, Robert E. ^[2]; Prakash, Louise ^[2]; Prakash, Satya ^[2]; Aggarwal, Aneel K. ^[1]

Icahn School of Medicine at Mount Sinai, New York, NY (United States)
Univ. of Texas Medical Branch, Galveston, TX (United States)

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 (Pol$$\iota$$) promotes error-free replication across 1-MeA. Steady state kinetic analyses indicate that Pol$$\iota$$ 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH)

OSTI ID:: 1430322

Alternate ID(s):: OSTI ID: 1409564

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Journal Issue: 1 Vol. 7; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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