5ulx
From Proteopedia
Structure of human DNA polymerase iota bound to template 1-methyl-deoxyadenosine crystallized in the presence of dCTP
Structural highlights
Function[POLI_HUMAN] Error-prone DNA polymerase specifically involved in DNA repair. Plays an important role in translesion synthesis, where the normal high-fidelity DNA polymerases cannot proceed and DNA synthesis stalls. Favors Hoogsteen base-pairing in the active site. Inserts the correct base with high-fidelity opposite an adenosine template. Exhibits low fidelity and efficiency opposite a thymidine template, where it will preferentially insert guanosine. May play a role in hypermutation of immunogobulin genes. Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but may not have lyase activity.[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedN1-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-iota (Poliota) promotes error-free replication across 1-MeA. Steady state kinetic analyses indicate that Poliota 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 Poliota 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 Poliota maintains discrimination between correct and incorrect incoming nucleotide opposite 1-MeA in preserving genome integrity. Mechanism of error-free DNA synthesis across N1-methyl-deoxyadenosine by human DNA polymerase-iota.,Jain R, Choudhury JR, Buku A, Johnson RE, Prakash L, Prakash S, Aggarwal AK Sci Rep. 2017 Mar 8;7:43904. doi: 10.1038/srep43904. PMID:28272441[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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