6Q02

Polymerase Eta-catalyzed insertion of the mismatched A opposite template cytarabine (AraC) residue

Summary for 6Q02

• Entry DOI: 10.2210/pdb6q02/pdb
• Related: 6PZ3
• Descriptor: DNA polymerase eta, DNA Primer Strand, DNA template containing a cytarabin (AraC) residue, ... (7 entities in total)
• Functional Keywords: lesion bypass, dna damage, dna replication, chemotherapy, transferase, transferase-dna complex, transferase/dna
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 55449.75

Authors

Rechkoblit, O.,Aggarwal, A.K. (deposition date: 2019-08-01, release date: 2019-11-20, Last modification date: 2023-10-11)

Primary citation

Rechkoblit, O.,Johnson, R.E.,Buku, A.,Prakash, L.,Prakash, S.,Aggarwal, A.K.
Structural insights into mutagenicity of anticancer nucleoside analog cytarabine during replication by DNA polymerase eta.
Sci Rep, 9:16400-16400, 2019

PubMed Abstract: Cytarabine (AraC) is the mainstay chemotherapy for acute myeloid leukemia (AML). Whereas initial treatment with AraC is usually successful, most AML patients tend to relapse, and AraC treatment-induced mutagenesis may contribute to the development of chemo-resistant leukemic clones. We show here that whereas the high-fidelity replicative polymerase Polδ is blocked in the replication of AraC, the lower-fidelity translesion DNA synthesis (TLS) polymerase Polη is proficient, inserting both correct and incorrect nucleotides opposite a template AraC base. Furthermore, we present high-resolution crystal structures of human Polη with a template AraC residue positioned opposite correct (G) and incorrect (A) incoming deoxynucleotides. We show that Polη can accommodate local perturbation caused by the AraC via specific hydrogen bonding and maintain a reaction-ready active site alignment for insertion of both correct and incorrect incoming nucleotides. Taken together, the structures provide a novel basis for the ability of Polη to promote AraC induced mutagenesis in relapsed AML patients.

PubMed: 31704958
DOI: 10.1038/s41598-019-52703-7

Experimental method

X-RAY DIFFRACTION (2.09 Å)