A mechanism for the exclusion of low-fidelity human Y-family DNA polymerases from base excision repair.
The human Y-family DNA polymerases, Poliota, Poleta, and Polkappa, function in promoting replication through DNA lesions. However, because of their low fidelity, any involvement of these polymerases in DNA synthesis during base excision repair (BER) would be highly mutagenic. Mechanisms, therefore, must exist to exclude their participation in BER. Here, we show that although Poliota, Poleta, and Polkappa are all able to form a covalent Schiff base intermediate with the 5'-deoxyribose phosphate (5'-dRP) residue that results from the incision of DNA at an abasic site by an AP endonuclease, they all lack the ability for the subsequent catalytic removal of the 5'-dRP group. Instead, the covalent trapping of these polymerases by the 5'-dRP residue inhibits their DNA synthetic activity during BER. The unprecedented ability of these polymerases for robust Schiff base formation without the release of the 5'-dRP product provides a means of preventing their participation in the DNA synthetic step of BER, thereby avoiding the high incidence of mutagenesis and carcinogenesis that would otherwise occur.
Haracska
Lajos
L
Sealy Center for Molecular Science, University of Texas Medical Branch at Galveston, Galveston, Texas 77555-1061, USA.
Prakash
Louise
L
Prakash
Satya
S
D004247:DNA / Q000378:metabolism*; D017931:DNA Primers / Q000737:chemistry; D004260:DNA Repair / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D005090:Exodeoxyribonucleases / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D019761:Phosphorus-Oxygen Lyases / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D012267:Ribosemonophosphates / Q000378:metabolism; D012545:Schiff Bases; D000094769:DNA Polymerase iota; D000099270:Y-Family DNA Polymerases
D004247:DNA; D017931:DNA Primers; D004259:DNA-Directed DNA Polymerase; D005090:Exodeoxyribonucleases; D005982:Glutathione Transferase; D019761:Phosphorus-Oxygen Lyases; D011993:Recombinant Fusion Proteins; D012267:Ribosemonophosphates; D012545:Schiff Bases; D000094769:DNA Polymerase iota; C058245:2-deoxyribose 5-phosphate; C423906:5'-deoxyribose phosphate lyase; C404302:POLK protein, human; D000099270:Y-Family DNA Polymerases; C112338:Rad30 protein; C000722070:POLI protein, human