6ak9 | pdb_00006ak9
Pre-catalytic Ternary Complex of Human DNA Polymerase Mu with Templating Cytosine and Incoming Ca-8oxodGTP
Structural highlights
Function[DPOLM_HUMAN] Gap-filling polymerase involved in repair of DNA double-strand breaks by non-homologous end joining (NHEJ). Participates in immunoglobulin (Ig) light chain gene rearrangement in V(D)J recombination.[1] [2] [3] [4] Publication Abstract from PubMedRecent research on the structure and mechanism of DNA polymerases has continued to generate fundamentally important features, including a noncanonical pathway involving "prebinding" of metal-bound dNTP (MdNTP) in the absence of DNA. While this noncanonical mechanism was shown to be a possible subset for African swine fever DNA polymerase X (Pol X) and human Pol lambda, it remains unknown whether it could be the primary pathway for a DNA polymerase. Pol mu is a unique member of the X-family with multiple functions and with unusual Mn(2+) preference. Here we report that Pol mu not only prebinds MdNTP in a catalytically active conformation but also exerts a Mn(2+) over Mg(2+) preference at this early stage of catalysis, for various functions: incorporation of dNTP into a single nucleotide gapped DNA, incorporation of rNTP in the nonhomologous end joining (NHEJ) repair, incorporation of dNTP to an ssDNA, and incorporation of an 8-oxo-dGTP opposite template dA (mismatched) or dC (matched). The structural basis of this noncanonical mechanism and Mn(2+) over Mg(2+) preference in these functions was analyzed by solving 19 structures of prebinding binary complexes, precatalytic ternary complexes, and product complexes. The results suggest that the noncanonical pathway is functionally relevant for the multiple functions of Pol mu. Overall, this work provides the structural and mechanistic basis for the long-standing puzzle in the Mn(2+) preference of Pol mu and expands the landscape of the possible mechanisms of DNA polymerases to include both mechanistic pathways. Human DNA Polymerase mu Can Use a Noncanonical Mechanism for Multiple Mn(2+)-Mediated Functions.,Chang YK, Huang YP, Liu XX, Ko TP, Bessho Y, Kawano Y, Maestre-Reyna M, Wu WJ, Tsai MD J Am Chem Soc. 2019 May 17. doi: 10.1021/jacs.9b01741. PMID:31067051[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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