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| Description
| - Reactive oxygen species constantly generated as by-products of cellular metabolism readily attack genomic DNA creating mutagenic lesions such as 7,8-dihydro-8-oxo-guanine (8-oxo-G) that promote aging. 8-oxo-G:A mispairs arising during DNA replication are eliminated by base excision repair initiated by the MutY DNA glycosylase homologue (MUTYH). Here, by using formaldehyde crosslinking in mammalian cell extracts, we demonstrate that the WRN helicase/exonuclease defective in the premature aging disorder Werner syndrome (WS) is recruited to DNA duplex containing an 8-oxo-G:A mispair in a manner dependent on DNA polymerase lambda (Pol lambda) that catalyzes accurate DNA synthesis over 8-oxo-G. Similarly, by immunofluorescence, we show that Pol lambda is required for accumulation of WRN at sites of 8-oxo-G lesions in human cells. Moreover, we show that nuclear focus formation of WRN and Pol lambda induced by oxidative stress is dependent on ongoing DNA replication and on the presence of MUTYH. Cell viability assays reveal that depletion of MUTYH suppresses the hypersensitivity of cells lacking WRN and/or Pol lambda to oxidative stress. Biochemical studies demonstrate that WRN binds to the catalytic domain of Pol lambda and specifically stimulates DNA gap filling by Pol lambda over 8-oxo-G followed by strand displacement synthesis. Our results suggest that WRN promotes long-patch DNA repair synthesis by Pol lambda during MUTYH-initiated repair of 8-oxo-G:A mispairs.
- Reactive oxygen species constantly generated as by-products of cellular metabolism readily attack genomic DNA creating mutagenic lesions such as 7,8-dihydro-8-oxo-guanine (8-oxo-G) that promote aging. 8-oxo-G:A mispairs arising during DNA replication are eliminated by base excision repair initiated by the MutY DNA glycosylase homologue (MUTYH). Here, by using formaldehyde crosslinking in mammalian cell extracts, we demonstrate that the WRN helicase/exonuclease defective in the premature aging disorder Werner syndrome (WS) is recruited to DNA duplex containing an 8-oxo-G:A mispair in a manner dependent on DNA polymerase lambda (Pol lambda) that catalyzes accurate DNA synthesis over 8-oxo-G. Similarly, by immunofluorescence, we show that Pol lambda is required for accumulation of WRN at sites of 8-oxo-G lesions in human cells. Moreover, we show that nuclear focus formation of WRN and Pol lambda induced by oxidative stress is dependent on ongoing DNA replication and on the presence of MUTYH. Cell viability assays reveal that depletion of MUTYH suppresses the hypersensitivity of cells lacking WRN and/or Pol lambda to oxidative stress. Biochemical studies demonstrate that WRN binds to the catalytic domain of Pol lambda and specifically stimulates DNA gap filling by Pol lambda over 8-oxo-G followed by strand displacement synthesis. Our results suggest that WRN promotes long-patch DNA repair synthesis by Pol lambda during MUTYH-initiated repair of 8-oxo-G:A mispairs. (en)
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| Title
| - Involvement of Werner syndrome protein in MUTYH-mediated repair of oxidative DNA damage
- Involvement of Werner syndrome protein in MUTYH-mediated repair of oxidative DNA damage (en)
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| skos:prefLabel
| - Involvement of Werner syndrome protein in MUTYH-mediated repair of oxidative DNA damage
- Involvement of Werner syndrome protein in MUTYH-mediated repair of oxidative DNA damage (en)
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| skos:notation
| - RIV/68378050:_____/12:00390248!RIV13-AV0-68378050
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| http://linked.open...avai/riv/aktivita
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| http://linked.open...avai/riv/aktivity
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| http://linked.open...iv/cisloPeriodika
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| http://linked.open...vai/riv/dodaniDat
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| http://linked.open...aciTvurceVysledku
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| http://linked.open.../riv/druhVysledku
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| http://linked.open...iv/duvernostUdaju
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| http://linked.open...titaPredkladatele
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| http://linked.open...dnocenehoVysledku
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| http://linked.open...ai/riv/idVysledku
| - RIV/68378050:_____/12:00390248
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| http://linked.open...riv/jazykVysledku
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| http://linked.open.../riv/klicovaSlova
| - DNA repair; oxidative stress; MUTYH; WRN; Pol lambda (en)
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| http://linked.open.../riv/klicoveSlovo
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| http://linked.open...odStatuVydavatele
| - GB - Spojené království Velké Británie a Severního Irska
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| http://linked.open...ontrolniKodProRIV
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| http://linked.open...i/riv/nazevZdroje
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| http://linked.open...in/vavai/riv/obor
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| http://linked.open...ichTvurcuVysledku
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| http://linked.open...cetTvurcuVysledku
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| http://linked.open...UplatneniVysledku
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| http://linked.open...v/svazekPeriodika
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| http://linked.open...iv/tvurceVysledku
| - Hübscher, U.
- Bohr, V. A.
- Burdová, Kamila
- Furrer, A.
- Janscak, P.
- Kanagaraj, R.
- König, C.
- Mihaljevic, B.
- Parasuraman, P.
- van Loon, B.
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| http://linked.open...ain/vavai/riv/wos
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| http://linked.open...n/vavai/riv/zamer
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| issn
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| number of pages
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| http://bibframe.org/vocab/doi
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