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Direct and indirect roles of RECQL4 in modulating base excision repair capacity
- Source :
- Human Molecular Genetics. 18:3470-3483
- Publication Year :
- 2009
- Publisher :
- Oxford University Press (OUP), 2009.
-
Abstract
- RECQL4 is a human RecQ helicase which is mutated in approximately two-thirds of individuals with Rothmund-Thomson syndrome (RTS), a disease characterized at the cellular level by chromosomal instability. BLM and WRN are also human RecQ helicases, which are mutated in Bloom and Werner's syndrome, respectively, and associated with chromosomal instability as well as premature aging. Here we show that primary RTS and RECQL4 siRNA knockdown human fibroblasts accumulate more H(2)O(2)-induced DNA strand breaks than control cells, suggesting that RECQL4 may stimulate repair of H(2)O(2)-induced DNA damage. RTS primary fibroblasts also accumulate more XRCC1 foci than control cells in response to endogenous or induced oxidative stress and have a high basal level of endogenous formamidopyrimidines. In cells treated with H(2)O(2), RECQL4 co-localizes with APE1, and FEN1, key participants in base excision repair. Biochemical experiments indicate that RECQL4 specifically stimulates the apurinic endonuclease activity of APE1, the DNA strand displacement activity of DNA polymerase beta, and incision of a 1- or 10-nucleotide flap DNA substrate by Flap Endonuclease I. Additionally, RTS cells display an upregulation of BER pathway genes and fail to respond like normal cells to oxidative stress. The data herein support a model in which RECQL4 regulates both directly and indirectly base excision repair capacity.
- Subjects :
- Guanine
DNA Repair
DNA repair
DNA damage
Flap structure-specific endonuclease 1
Biology
XRCC1
DNA-(Apurinic or Apyrimidinic Site) Lyase
Genetics
Humans
RNA, Small Interfering
Flap endonuclease
Molecular Biology
Cells, Cultured
DNA Polymerase beta
Genetics (clinical)
Oligonucleotide Array Sequence Analysis
RecQ Helicases
Rothmund-Thomson Syndrome
Hydrogen Peroxide
Articles
General Medicine
Base excision repair
DNA-(apurinic or apyrimidinic site) lyase
Molecular biology
DNA-Binding Proteins
Pyrimidines
X-ray Repair Cross Complementing Protein 1
Biocatalysis
DNA Damage
Nucleotide excision repair
Subjects
Details
- ISSN :
- 14602083 and 09646906
- Volume :
- 18
- Database :
- OpenAIRE
- Journal :
- Human Molecular Genetics
- Accession number :
- edsair.doi.dedup.....28a76d3393910425b368c68abab4d533