Human nucleotide excision nuclease removes thymine dimers from DNA by incising the 22nd phosphodiester bond 5' and the 6th phosphodiester bond 3' to the photodimer.

Huang, Juch-Chin; Svoboda, Daniel; Reardon, Joyce T.; Sancar, Aziz

doi:10.1073/pnas.89.8.3664

Cited by 416 publications

(311 citation statements)

References 32 publications

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“…To determine whether the circadian time affects nucleotide excision repair activity in mice, we harvested several organs at ZT06 and ZT18 (ZT0 is time of light-on under a 12-h light:12-h dark lighting regimen) and tested them for nucleotide excision repair activity. We used the highly sensitive and specific ''excision assay'' (7,8) to measure repair (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

Circadian oscillation of nucleotide excision repair in mammalian brain

Kang

Reardon

Kemp

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

186

196

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The circadian clock regulates the daily rhythms in the physiology and behavior of many organisms, including mice and humans. These cyclical changes at molecular and macroscopic levels affect the organism's response to environmental stimuli such as light and food intake and the toxicity and efficacy of chemo-and radiotherapeutic agents. In this work, we investigated the circadian behavior of the nucleotide excision repair capacity in the mouse cerebrum to gain some insight into the optimal circadian time for favorable therapeutic response with minimal side effects in cancer treatment with chemotherapeutic drugs that produce bulky adducts in DNA. We find that nucleotide excision repair activity in the mouse cortex is highest in the afternoon/evening hours and is at its lowest in the night/early morning hours. The circadian oscillation of the repair capacity is caused at least in part by the circadian oscillation of the xeroderma pigmentosum A DNA damage recognition protein.cancer treatment ͉ chronotherapy ͉ circadian clock ͉ xeroderma pigmentosum A C ircadian rhythm is the daily oscillation in the biochemical, behavioral, and physiological functions of organisms (1, 2). Circadian clock disruption by environmental factors and behavioral patterns has been implicated as a contributing factor in carcinogenesis (2-4). Similarly, a limited number of studies have indicated that the efficacy of chemo-and radiotherapy of cancer and the side effects of these treatments are markedly influenced by the circadian time of administration of these agents (4, 5). Although attempts have been made to put these findings to practice in preventive and clinical medicine, the empirical nature of the observations and the lack of mechanistic explanations for the findings have been serious obstacles to making use of these findings in cancer prevention and treatment.Important progress in the past decade has provided a reasonably detailed model for the mammalian circadian clock. In mice and humans, the clock is present in essentially every cell and is generated by an autoregulatory transcription-translation feedback loop (TTFL) (1, 2): Clock and Bmal1 transcription factors bind to the E-box promoter elements of the Cryptochrome (Cry)1 and 2 and Period (Per)1 and 2 genes and activate their transcription. The Cry and Per proteins make oligomeric complexes that, after a time delay, inhibit the Clock⅐Bmal1 complex and hence the transcription of the Cry and Per genes. The time delay between the synthesis of Cry and Per and their action as repressors generates an oscillatory pattern of expression of Crys and Pers and other clock controlled genes that are regulated by Clock⅐Bmal1 but are not part of the TTFL. It is this oscillation of gene expression that affects cellular and organismic function to give rise to the circadian rhythm at a macroscopic level. These peripheral circadian oscillations are synchronized with one another by the master circadian clock that is located above the optic chiasma, in the suprachiasmatic nuclei (SCN). The SCN coordina...

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Section: Resultsmentioning

confidence: 99%

Circadian oscillation of nucleotide excision repair in mammalian brain

Kang

Reardon

Kemp

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

186

196

View full text Add to dashboard Cite

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“…It is an alternative to several other methods for detecting the dual incision events of NER. A conceptually straightforward approach is to incorporate an internal 32 P-labelled nucleotide near the adduct site, directly observing the ladder of excised oligonucleotides after puri®cation of the reaction product (Huang et al, 1992;Hess et al, 1997). The advantages of this method are that it can be applied to any lesion and is directly quanti®able.…”

Section: Rapid Methods For Detecting Dual Incisions During Nermentioning

confidence: 99%

Resistance of human nucleotide excision repair synthesis in vitro to p21Cdn1

et al. 1998

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The p21 Cdn1 protein (cip1/waf1/sdi1) plays an important role as an inhibitor of mammalian cell proliferation in response to DNA damage. By interacting with and inhibiting the function of cyclin-Cdk complexes, p21 can block entry into S phase. p21 can also directly inhibit replicative DNA synthesis by binding to the DNA polymerase sliding clamp factor PCNA. When cells are damaged and p21 is induced, DNA nucleotide excision repair (NER) continues, even though this pathway is PCNA-dependent. We investigated features of p21-resistant NER using human cell extracts. A direct endlabelling approach was used to measure the excision of damaged oligonucleotides by NER and no inhibition by p21 was found. By contrast, ®lling of the *30 nt gaps created by NER could be inhibited by pre-binding p21 to PCNA, but only when gap ®lling was uncoupled from incision. Binding p21 to PCNA could also inhibit ®lling of model 30 nt gaps by both puri®ed DNA polymerases d and e. When p21 was incubated in a cell extract before addition of PCNA, inhibition of repair synthesis was gradually relieved with time. This incubation gives p21 the opportunity to associate with other targets. As p21 blocks association of DNA polymerases with PCNA but does not prevent loading of PCNA onto DNA, repair gap ®lling can occur rapidly as soon as p21 dissociates from PCNA. A synthetic PCNA-binding p21 peptide was an e cient inhibitor of NER synthesis in cell extracts.

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“…The 5' incision by XPF-ERCC1 precedes the 3' incision by XPG [21]. Through double cleavage of 6 the damaged strand, the combined action of these two endonucleases leads to excision of the offending lesion in the form of an oligonucleotide segment of 24-32 residues [22,23]. Duplex integrity is reestablished by the action of DNA polymerases δ, ε and κ [24,25], in conjunction with RFC and PCNA.…”

Section: Overview Of the Ggr Pathwaymentioning

confidence: 99%