Translesion synthesis past platinum DNA adducts by human DNA polymerase mu.
DNA polymerase mu (pol mu) is a member of the pol X family of DNA polymerases, and it shares a number of characteristics of both DNA polymerase beta (pol beta) and terminal deoxynucleotidyl transferase (TdT). Because pol beta has been shown to perform translesion DNA synthesis past cisplatin (CP)- and oxaliplatin (OX)-GG adducts, we determined the ability of pol mu to bypass these lesions. Pol mu bypassed CP and OX adducts with an efficiency of 14-35% compared to chain elongation on undamaged DNA, which is second only to pol eta in terms of bypass efficiency. The relative ability of pol mu to bypass CP and OX adducts was dependent on both template structure and sequence context. Since pol mu has been shown to be more efficient on gapped DNA templates than on primed single-stranded DNA templates, we determined the ability of pol mu to bypass Pt-DNA adducts on both primed single-stranded and gapped templates. The bypass of Pt-DNA adducts by pol mu was highly error-prone on all templates, resulting in 2, 3, and 4 nt deletions. We postulate that bypass of Pt-DNA adducts by pol mu may involve looping out the Pt-GG adduct to allow chain elongation downstream of the adduct. This reaction appears to be facilitated by the presence of a downstream "acceptor" and a gap large enough to provide undamaged template DNA for elongation past the adduct, although gapped DNA is clearly not required for bypass.
Havener
Jody M
JM
Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7260, USA.
Nick McElhinny
Stephanie A
SA
Bassett
Ekaterina
E
Gauger
Michele
M
Ramsden
Dale A
DA
Chaney
Stephen G
SG
D002384:Catalysis; D002945:Cisplatin / Q000737:chemistry* / Q000633:toxicity; D018736:DNA Adducts / Q000737:chemistry*; D004249:DNA Damage; D017931:DNA Primers / Q000737:chemistry; D004277:DNA, Single-Stranded / Q000096:biosynthesis*; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry*; D003838:Deoxyadenine Nucleotides / Q000737:chemistry; D003848:Deoxyguanine Nucleotides / Q000737:chemistry; D006150:Guanine Nucleotides / Q000737:chemistry; D006801:Humans; D009841:Oligonucleotides / Q000737:chemistry; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000633:toxicity; D000077150:Oxaliplatin; D013698:Templates, Genetic; D013942:Thymine Nucleotides / Q000737:chemistry
D018736:DNA Adducts; D017931:DNA Primers; D004277:DNA, Single-Stranded; D003838:Deoxyadenine Nucleotides; D003848:Deoxyguanine Nucleotides; D006150:Guanine Nucleotides; D009841:Oligonucleotides; D009944:Organoplatinum Compounds; D013942:Thymine Nucleotides; D000077150:Oxaliplatin; C029603:deoxyguanosine triphosphate; C407743:DNA polymerase mu; D004259:DNA-Directed DNA Polymerase; C026600:2'-deoxyadenosine triphosphate; D002945:Cisplatin; C024157:thymidine 5'-triphosphate