Role for DNA Polymerase κ in the Processing of N2-N2-Guanine Interstrand Cross-links
Although there exists compelling genetic evidence for a homologous recombination-independent pathway for repair of interstrand cross-links (ICLs) involving translesion synthesis (TLS), biochemical support for this model is lacking. To identify DNA polymerases that may function in TLS past ICLs, olig...
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container_start_page | 17075 |
container_title | The Journal of biological chemistry |
container_volume | 283 |
creator | Irina G. Minko Michael B. Harbut Ivan D. Kozekov Albena Kozekova Petra M. Jakobs Susan B. Olson Robb E. Moses Thomas M. Harris Carmelo J. Rizzo R. Stephen Lloyd |
description | Although there exists compelling genetic evidence for a homologous recombination-independent pathway for repair of interstrand
cross-links (ICLs) involving translesion synthesis (TLS), biochemical support for this model is lacking. To identify DNA polymerases
that may function in TLS past ICLs, oligodeoxynucleotides were synthesized containing site-specific ICLs in which the linkage
was between N 2 -guanines, similar to cross-links formed by mitomycin C and enals. Here, data are presented that mammalian cell replication
of DNAs containing these lesions was â¼97% accurate. Using a series of oligodeoxynucleotides that mimic potential intermediates
in ICL repair, we demonstrate that human polymerase (pol) κ not only catalyzed accurate incorporation opposite the cross-linked
guanine but also replicated beyond the lesion, thus providing the first biochemical evidence for TLS past an ICL. The efficiency
of TLS was greatly enhanced by truncation of both the 5 â² and 3 â² ends of the nontemplating strand. Further analyses showed
that although yeast Rev1 could incorporate a dCTP opposite the cross-linked guanine, no evidence was found for TLS by pol
ζ or a pol ζ/Rev1 combination. Because pol κ was able to bypass these ICLs, biological evidence for a role for pol κ in tolerating
the N 2 - N 2 -guanine ICLs was sought; both cell survival and chromosomal stability were adversely affected in pol κ-depleted cells following
mitomycin C exposure. Thus, biochemical data and cellular studies both suggest a role for pol κ in the processing of N 2 - N 2 -guanine ICLs. |
doi_str_mv | 10.1074/jbc.M801238200 |
format | Article |
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cross-links (ICLs) involving translesion synthesis (TLS), biochemical support for this model is lacking. To identify DNA polymerases
that may function in TLS past ICLs, oligodeoxynucleotides were synthesized containing site-specific ICLs in which the linkage
was between N 2 -guanines, similar to cross-links formed by mitomycin C and enals. Here, data are presented that mammalian cell replication
of DNAs containing these lesions was â¼97% accurate. Using a series of oligodeoxynucleotides that mimic potential intermediates
in ICL repair, we demonstrate that human polymerase (pol) κ not only catalyzed accurate incorporation opposite the cross-linked
guanine but also replicated beyond the lesion, thus providing the first biochemical evidence for TLS past an ICL. The efficiency
of TLS was greatly enhanced by truncation of both the 5 â² and 3 â² ends of the nontemplating strand. Further analyses showed
that although yeast Rev1 could incorporate a dCTP opposite the cross-linked guanine, no evidence was found for TLS by pol
ζ or a pol ζ/Rev1 combination. Because pol κ was able to bypass these ICLs, biological evidence for a role for pol κ in tolerating
the N 2 - N 2 -guanine ICLs was sought; both cell survival and chromosomal stability were adversely affected in pol κ-depleted cells following
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cross-links (ICLs) involving translesion synthesis (TLS), biochemical support for this model is lacking. To identify DNA polymerases
that may function in TLS past ICLs, oligodeoxynucleotides were synthesized containing site-specific ICLs in which the linkage
was between N 2 -guanines, similar to cross-links formed by mitomycin C and enals. Here, data are presented that mammalian cell replication
of DNAs containing these lesions was â¼97% accurate. Using a series of oligodeoxynucleotides that mimic potential intermediates
in ICL repair, we demonstrate that human polymerase (pol) κ not only catalyzed accurate incorporation opposite the cross-linked
guanine but also replicated beyond the lesion, thus providing the first biochemical evidence for TLS past an ICL. The efficiency
of TLS was greatly enhanced by truncation of both the 5 â² and 3 â² ends of the nontemplating strand. Further analyses showed
that although yeast Rev1 could incorporate a dCTP opposite the cross-linked guanine, no evidence was found for TLS by pol
ζ or a pol ζ/Rev1 combination. Because pol κ was able to bypass these ICLs, biological evidence for a role for pol κ in tolerating
the N 2 - N 2 -guanine ICLs was sought; both cell survival and chromosomal stability were adversely affected in pol κ-depleted cells following
mitomycin C exposure. Thus, biochemical data and cellular studies both suggest a role for pol κ in the processing of N 2 - N 2 -guanine ICLs.</description><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid/><recordid>eNqNirFOwzAQQC0EoimwMt_A6vbOThR3RAUKA1WFkGCL0nBpXFJb8gUhfoIPYoQfowMfwNOT3vKUOiecEJb5dLtuJvcOyVhnEA9URuistgU9H6oM0ZCemcKN1Fhki3vyGR2rEbnc5pZspp4eYs_QxgRXy0tYxf5jx6kWhp_P7y_wAYaOYZViwyI-bCC2sDR67-KtDj4w3IWBkwypDi8wT1FE9z68yqk6aute-OyvJ-ri5vpxfqs7v-nefeJq7WPT8a4yzlamqKjEsrD_3H4BAWtJQQ</recordid><startdate>20080620</startdate><enddate>20080620</enddate><creator>Irina G. Minko</creator><creator>Michael B. Harbut</creator><creator>Ivan D. Kozekov</creator><creator>Albena Kozekova</creator><creator>Petra M. Jakobs</creator><creator>Susan B. Olson</creator><creator>Robb E. Moses</creator><creator>Thomas M. Harris</creator><creator>Carmelo J. Rizzo</creator><creator>R. Stephen Lloyd</creator><general>American Society for Biochemistry and Molecular Biology</general><scope/></search><sort><creationdate>20080620</creationdate><title>Role for DNA Polymerase κ in the Processing of N2-N2-Guanine Interstrand Cross-links</title><author>Irina G. Minko ; Michael B. Harbut ; Ivan D. Kozekov ; Albena Kozekova ; Petra M. Jakobs ; Susan B. Olson ; Robb E. Moses ; Thomas M. Harris ; Carmelo J. Rizzo ; R. Stephen Lloyd</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-highwire_biochem_283_25_170753</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Irina G. Minko</creatorcontrib><creatorcontrib>Michael B. Harbut</creatorcontrib><creatorcontrib>Ivan D. Kozekov</creatorcontrib><creatorcontrib>Albena Kozekova</creatorcontrib><creatorcontrib>Petra M. Jakobs</creatorcontrib><creatorcontrib>Susan B. Olson</creatorcontrib><creatorcontrib>Robb E. Moses</creatorcontrib><creatorcontrib>Thomas M. Harris</creatorcontrib><creatorcontrib>Carmelo J. Rizzo</creatorcontrib><creatorcontrib>R. Stephen Lloyd</creatorcontrib><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Irina G. Minko</au><au>Michael B. Harbut</au><au>Ivan D. Kozekov</au><au>Albena Kozekova</au><au>Petra M. Jakobs</au><au>Susan B. Olson</au><au>Robb E. Moses</au><au>Thomas M. Harris</au><au>Carmelo J. Rizzo</au><au>R. Stephen Lloyd</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Role for DNA Polymerase κ in the Processing of N2-N2-Guanine Interstrand Cross-links</atitle><jtitle>The Journal of biological chemistry</jtitle><date>2008-06-20</date><risdate>2008</risdate><volume>283</volume><issue>25</issue><spage>17075</spage><pages>17075-</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Although there exists compelling genetic evidence for a homologous recombination-independent pathway for repair of interstrand
cross-links (ICLs) involving translesion synthesis (TLS), biochemical support for this model is lacking. To identify DNA polymerases
that may function in TLS past ICLs, oligodeoxynucleotides were synthesized containing site-specific ICLs in which the linkage
was between N 2 -guanines, similar to cross-links formed by mitomycin C and enals. Here, data are presented that mammalian cell replication
of DNAs containing these lesions was â¼97% accurate. Using a series of oligodeoxynucleotides that mimic potential intermediates
in ICL repair, we demonstrate that human polymerase (pol) κ not only catalyzed accurate incorporation opposite the cross-linked
guanine but also replicated beyond the lesion, thus providing the first biochemical evidence for TLS past an ICL. The efficiency
of TLS was greatly enhanced by truncation of both the 5 â² and 3 â² ends of the nontemplating strand. Further analyses showed
that although yeast Rev1 could incorporate a dCTP opposite the cross-linked guanine, no evidence was found for TLS by pol
ζ or a pol ζ/Rev1 combination. Because pol κ was able to bypass these ICLs, biological evidence for a role for pol κ in tolerating
the N 2 - N 2 -guanine ICLs was sought; both cell survival and chromosomal stability were adversely affected in pol κ-depleted cells following
mitomycin C exposure. Thus, biochemical data and cellular studies both suggest a role for pol κ in the processing of N 2 - N 2 -guanine ICLs.</abstract><pub>American Society for Biochemistry and Molecular Biology</pub><pmid>18434313</pmid><doi>10.1074/jbc.M801238200</doi></addata></record> |
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title | Role for DNA Polymerase κ in the Processing of N2-N2-Guanine Interstrand Cross-links |
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