TY - JOUR
T1 - A mechanism for the exclusion of low-fidelity human Y-family DNA polymerases from base excision repair
AU - Haracska, Lajos
AU - Prakash, Louise
AU - Prakash, Satya
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2003/11/15
Y1 - 2003/11/15
N2 - The human Y-family DNA polymerases, Polι, Polη, and Polκ, 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 Polι, Polη, and Polκ 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.
AB - The human Y-family DNA polymerases, Polι, Polη, and Polκ, 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 Polι, Polη, and Polκ 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.
KW - 5′-dRP lyase
KW - 5′-doexyribose phosphate
KW - Abasic site
KW - Base excision repair
KW - Y-family DNA polymerases
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U2 - 10.1101/gad.1146103
DO - 10.1101/gad.1146103
M3 - Article
C2 - 14630940
AN - SCOPUS:0344011559
SN - 0890-9369
VL - 17
SP - 2777
EP - 2785
JO - Genes and Development
JF - Genes and Development
IS - 22
ER -