Highly error-free role of DNA polymerase η in the replicative bypass of UV-induced pyrimidine dimers in mouse and human cells

Jung Hoon Yoon, Louise Prakash, Satya Prakash

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94 Citations (Scopus)

Abstract

Cyclobutane pyrimidine dimers (CPDs) constitute the most frequent UV-induced DNA photoproduct. However, it has remained unclear how human and other mammalian cells mitigate the mutagenic and carcinogenic potential of CPDs emanating from their replicative bypass. Here, we examine in human cells the roles of translesion synthesis (TLS) DNA polymerases (Pols) in the replicative bypass of a cis-syn TT dimer carried on the leading or the lagging strand DNA template in a plasmid system we have designed, and we determine in mouse cells the frequencies and mutational spectra generated from TLS occurring specifically opposite CPDs formed at TT, TC, and CC dipyrimidine sites. From these studies we draw the following conclusions: (i) TLS makes a very prominent contribution to CPD bypass on both the DNA strands during replication; (ii) Pols η, κ, and ζ provide alternate pathways for TLS opposite CPDs wherein Pols κ and ζ promote mutagenic TLS opposite CPDs; and (iii) the absence of mutagenic TLS events opposite a cis-syn TT dimer in human cells and opposite CPDs formed at TT, TC, and CC sites in mouse cells that we observe upon the simultaneous knockdown of Pols κ and ζ implicates a highly error-free role of Polη in TLS opposite CPDs in mammalian cells. Such a remarkably high in vivo fidelity of Polη could not have been anticipated in view of its low intrinsic fidelity. These observations have important bearing on how mammalian cells have adapted to avoid the mutagenic and carcinogenic consequences of exposure to sunlight.

Original languageEnglish (US)
Pages (from-to)18219-18224
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number43
DOIs
StatePublished - 2009

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Pyrimidine Dimers
DNA-Directed DNA Polymerase
DNA
Sunlight
Plasmids

Keywords

  • DNA damage and repair
  • Translesion synthesis
  • UV damage

ASJC Scopus subject areas

  • General

Cite this

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title = "Highly error-free role of DNA polymerase η in the replicative bypass of UV-induced pyrimidine dimers in mouse and human cells",
abstract = "Cyclobutane pyrimidine dimers (CPDs) constitute the most frequent UV-induced DNA photoproduct. However, it has remained unclear how human and other mammalian cells mitigate the mutagenic and carcinogenic potential of CPDs emanating from their replicative bypass. Here, we examine in human cells the roles of translesion synthesis (TLS) DNA polymerases (Pols) in the replicative bypass of a cis-syn TT dimer carried on the leading or the lagging strand DNA template in a plasmid system we have designed, and we determine in mouse cells the frequencies and mutational spectra generated from TLS occurring specifically opposite CPDs formed at TT, TC, and CC dipyrimidine sites. From these studies we draw the following conclusions: (i) TLS makes a very prominent contribution to CPD bypass on both the DNA strands during replication; (ii) Pols η, κ, and ζ provide alternate pathways for TLS opposite CPDs wherein Pols κ and ζ promote mutagenic TLS opposite CPDs; and (iii) the absence of mutagenic TLS events opposite a cis-syn TT dimer in human cells and opposite CPDs formed at TT, TC, and CC sites in mouse cells that we observe upon the simultaneous knockdown of Pols κ and ζ implicates a highly error-free role of Polη in TLS opposite CPDs in mammalian cells. Such a remarkably high in vivo fidelity of Polη could not have been anticipated in view of its low intrinsic fidelity. These observations have important bearing on how mammalian cells have adapted to avoid the mutagenic and carcinogenic consequences of exposure to sunlight.",
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author = "Yoon, {Jung Hoon} and Louise Prakash and Satya Prakash",
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AU - Yoon, Jung Hoon

AU - Prakash, Louise

AU - Prakash, Satya

PY - 2009

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N2 - Cyclobutane pyrimidine dimers (CPDs) constitute the most frequent UV-induced DNA photoproduct. However, it has remained unclear how human and other mammalian cells mitigate the mutagenic and carcinogenic potential of CPDs emanating from their replicative bypass. Here, we examine in human cells the roles of translesion synthesis (TLS) DNA polymerases (Pols) in the replicative bypass of a cis-syn TT dimer carried on the leading or the lagging strand DNA template in a plasmid system we have designed, and we determine in mouse cells the frequencies and mutational spectra generated from TLS occurring specifically opposite CPDs formed at TT, TC, and CC dipyrimidine sites. From these studies we draw the following conclusions: (i) TLS makes a very prominent contribution to CPD bypass on both the DNA strands during replication; (ii) Pols η, κ, and ζ provide alternate pathways for TLS opposite CPDs wherein Pols κ and ζ promote mutagenic TLS opposite CPDs; and (iii) the absence of mutagenic TLS events opposite a cis-syn TT dimer in human cells and opposite CPDs formed at TT, TC, and CC sites in mouse cells that we observe upon the simultaneous knockdown of Pols κ and ζ implicates a highly error-free role of Polη in TLS opposite CPDs in mammalian cells. Such a remarkably high in vivo fidelity of Polη could not have been anticipated in view of its low intrinsic fidelity. These observations have important bearing on how mammalian cells have adapted to avoid the mutagenic and carcinogenic consequences of exposure to sunlight.

AB - Cyclobutane pyrimidine dimers (CPDs) constitute the most frequent UV-induced DNA photoproduct. However, it has remained unclear how human and other mammalian cells mitigate the mutagenic and carcinogenic potential of CPDs emanating from their replicative bypass. Here, we examine in human cells the roles of translesion synthesis (TLS) DNA polymerases (Pols) in the replicative bypass of a cis-syn TT dimer carried on the leading or the lagging strand DNA template in a plasmid system we have designed, and we determine in mouse cells the frequencies and mutational spectra generated from TLS occurring specifically opposite CPDs formed at TT, TC, and CC dipyrimidine sites. From these studies we draw the following conclusions: (i) TLS makes a very prominent contribution to CPD bypass on both the DNA strands during replication; (ii) Pols η, κ, and ζ provide alternate pathways for TLS opposite CPDs wherein Pols κ and ζ promote mutagenic TLS opposite CPDs; and (iii) the absence of mutagenic TLS events opposite a cis-syn TT dimer in human cells and opposite CPDs formed at TT, TC, and CC sites in mouse cells that we observe upon the simultaneous knockdown of Pols κ and ζ implicates a highly error-free role of Polη in TLS opposite CPDs in mammalian cells. Such a remarkably high in vivo fidelity of Polη could not have been anticipated in view of its low intrinsic fidelity. These observations have important bearing on how mammalian cells have adapted to avoid the mutagenic and carcinogenic consequences of exposure to sunlight.

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