Genetic interaction between DNA polymerase β and DNA-PKcs in embryogenesis and neurogenesis

Niimi, Naoko; Sugo, Noriyuki; Aratani, Yasuaki; Koyama, Hideki

doi:10.1038/sj.cdd.4401543

Cited by 19 publications

(13 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Associated studies using a parp (−/−) pol β (−/−) mouse resulted in a more severe neural phenotype (Sugo et al 2007) seen also with a DNA-PKcs (−/−) pol β (−/−) mouse (Niimi et al 2005). An assessment of mutational frequency found that the pol β (−/−) animals actually had lower levels of mutation in the brain then WT litter mates, proposed to be the result of increased apoptosis that clears damaged neurons (Niimi et al 2006).…”

Section: Dna Polymerase βmentioning

confidence: 99%

Base excision repair in the mammalian brain: Implication for age related neurodegeneration

Sýkora

Wilson

Bohr

2013

Mechanisms of Ageing and Development

View full text Add to dashboard Cite

The repair of damaged DNA is essential to maintain longevity of an organism. The brain is a matrix of different neural cell types including proliferative astrocytes and post-mitotic neurons. Post-mitotic DNA repair is a version of proliferative DNA repair, with a reduced number of available pathways and most of these attenuated. Base Excision Repair (BER) is one pathway that remains robust in neurons; it is this pathway that resolves the damage due to oxidative stress. This oxidative damage is an unavoidable byproduct of respiration, and considering the high metabolic activity of neurons this type of damage is particularly pertinent in the brain. The accumulation of oxidative DNA damage over time is a central aspect of the theory of aging and repair of such chronic damage is of the highest importance. We review research conducted in BER mouse models to clarify the role of this pathway in the neural system. The requirement for BER in proliferating cells also correlates with high levels of many of the BER enzymes in neurogenesis after DNA damage. However, the pathway is also necessary for normal neural maintenance as larger infarct volumes after ischemic stroke are seen in some glycosylase deficient animals. Further, the requirement for DNA polymerase β in post-mitotic BER is potentially more important than in proliferating cells due to reduced levels of replicative polymerases. The BER response may have particular relevance for the onset and progression of many neurodegenerative diseases associated with an increase in oxidative stress including Alzheimer’s.

show abstract

Section: Dna Polymerase βmentioning

confidence: 99%

Base excision repair in the mammalian brain: Implication for age related neurodegeneration

Sýkora

Wilson

Bohr

2013

Mechanisms of Ageing and Development

View full text Add to dashboard Cite

show abstract

“…Characterization of the pol β knockout mouse [29,30] [34,54,55]; among other studies too numerous to mention herein. The most definitive and reproducible endpoint that has been used to evaluate pol β *To whom correspondence should be addressed: Robert W. Sobol, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Research Pavilion, Suite 2.6, 5117 Centre Avenue, Pittsburgh, PA 15213-1863, Phone: 412-623-7764, Fax: 412-623-7761, e-mail: rws9@pitt.edu.…”

Section: Dear Editormentioning

confidence: 99%

“…Several groups reported complete BER in vitro with pol β and additional purified proteins [22,23,25]. Although it was demonstrated in heterologous systems (E. coli and Saccharomyces cerevisiae) that pol β can conduct DNA replication and repair in vivo [26,27], it was not until a mouse gene knockout was made that the specificity of the repair conducted by pol β was defined [28].Characterization of the pol β knockout mouse [29,30] [34,54,55]; among other studies too numerous to mention herein. The most definitive and reproducible endpoint that has been used to evaluate pol β *To whom correspondence should be addressed: Robert W. Sobol, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Research Pavilion, Suite 2.6, 5117 Centre Avenue, Pittsburgh, PA 15213-1863, Phone: 412-623-7764, Fax: 412-623-7761, e-mail: rws9@pitt.edu.…”

mentioning

confidence: 99%

DNA polymerase beta null mouse embryonic fibroblasts harbor a homozygous null mutation in DNA polymerase iota

Sobol

2007

DNA Repair

View full text Add to dashboard Cite

Dear EditorPrior to the explosion of gene targeting technology, considerable biochemical and cell-based experiments suggested a role for DNA polymerase β (pol β) in DNA repair. Since its initial discovery in 1971 [1], the enzyme that was to eventually be designated pol β [2,3] was unique in its enzymatic properties [4][5][6] as compared to the other newly characterized mammalian DNA polymerases alpha (pol α), gamma (pol γ) and delta (polδ) [1,7]. Of the four eukaryotic DNA polymerases identified by 1977, pol β soon earned the moniker of 'the' DNA repair polymerase [8][9][10][11]. These early studies defined a role for pol β in repair using isolated nuclei or nuclear extracts, monitoring the incorporation of radioactive nucleosides following ultraviolet (UV) light-induced DNA damage [8][9][10][11]. A more definitive role for pol β in excision repair in vitro was demonstrated in 1983, in which complete removal of pyrimidine dimers in DNA was conducted by purified enzyme preparations of pol β, T4 denV (UV endonuclease) and HeLa AP endonuclease II [12]. Although it was subsequently shown that pol α can also carry-out gap-filling DNA synthesis in a base excision repair (BER) reaction [13], the evidence continued to mount in support of pol β acting as 'the' DNA repair polymerase in the nucleus, while pol γ participated in replication and repair in mitochondria [1]. Studies continued to identify a role for pol β in the repair of damage induced by many different DNA damaging agents, including bleomycin [14,15] [21][22][23][24]. Several groups reported complete BER in vitro with pol β and additional purified proteins [22,23,25]. Although it was demonstrated in heterologous systems (E. coli and Saccharomyces cerevisiae) that pol β can conduct DNA replication and repair in vivo [26,27], it was not until a mouse gene knockout was made that the specificity of the repair conducted by pol β was defined [28].Characterization of the pol β knockout mouse [29,30] [34,54,55]; among other studies too numerous to mention herein. The most definitive and reproducible endpoint that has been used to evaluate pol β *To whom correspondence should be addressed: Robert W. Sobol, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Research Pavilion, Suite 2.6, 5117 Centre Avenue, Pittsburgh, PA 15213-1863, Phone: 412-623-7764, Fax: 412-623-7761, e-mail: rws9@pitt.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript participation in repair in vivo is survival following DNA damage such as exposure to alkylating agen...

show abstract

“…Consequently, the functions of DNA-PKcs during neurogenesis remain unclear. Evidence suggests DNA-PKcs loss leads to significantly greater levels of DNA damage induced cell death in cortical neurons, with subsequent loss of PolBeta, and in response to excitotoxic injury (Chechlacz, Vemuri et al 2001, Vemuri, Schiller et al 2001, Neema, Navarro-Quiroga et al 2005, Niimi, Sugo et al 2005.…”

Section: Mouse Modelsmentioning

confidence: 99%

“…In contrast to humans, DNA-PKcs function in mice is dispensable for NHEJ (Gu, Sekiguchi et al 2000, Douglas, Gupta et al 2005. Consequently, DNA-PKcs function during neurogenesis is controversial with evidence suggesting DNA-PKcs loss leads to significantly higher levels of DNA damage induced p53-dependent cell death alone, with subsequent loss of PolBeta, and in response to excitotoxic injury (Chechlacz, Vemuri et al 2001, Vemuri, Schiller et al 2001, Neema, Navarro-Quiroga et al 2005, Niimi, Sugo et al 2005. Additionally, DNA-PKcs has been ascribed to a variety of apparent non-DNA-damage related roles , Rajagopalan, Moyle et al 2010, Kong, Shen et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Integration of ATM, ATR, and DNA-PKcs Signaling Maintains Genome Integrity During Neurogenesis

Enriquez-Rios¹

View full text Add to dashboard Cite

show abstract

Genetic interaction between DNA polymerase β and DNA-PKcs in embryogenesis and neurogenesis

Cited by 19 publications

References 53 publications

Base excision repair in the mammalian brain: Implication for age related neurodegeneration

Base excision repair in the mammalian brain: Implication for age related neurodegeneration

DNA polymerase beta null mouse embryonic fibroblasts harbor a homozygous null mutation in DNA polymerase iota

Integration of ATM, ATR, and DNA-PKcs Signaling Maintains Genome Integrity During Neurogenesis

Contact Info

Product

Resources

About