Homologous Recombination but Not Nucleotide Excision Repair Plays a Pivotal Role in Tolerance of DNA-Protein Cross-links in Mammalian Cells

Nakano, Toshiaki; Katafuchi, Atsushi; Matsubara, Miyao; Terato, Hiroaki; Tsuboi, Tomohiro; Masuda, Tasuku; Tatsumoto, Takahiro; Pack, Seung Pil; Makino, Keisuke; Croteau, Deborah L.; Houten, Bennett Van; Iijima, Kenta; Tauchi, Hiroshi; Ide, Hiroshi

doi:10.1074/jbc.m109.019174

Cited by 118 publications

(182 citation statements)

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“…The pyrimidine ring modification of decitabine subsequently depletes DNMT1 and can also directly hypomethylate DNA, since it cannot accept a methyl group (33,34). High decitabine concentrations, however, do have antimetabolic, DNA-damaging cytotoxic effects (35)(36)(37). Moreover, aggressive DNA-damaging cytotoxic therapy, despite the risk of treatment-related mortality, cures some myeloid cancers (e.g., AML subtypes that do not have p53 system abnormalities); this suggested that cytotoxicity could be the key to durable remissions.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of noncytotoxic DNMT1-depleting therapy in patients with myelodysplastic syndromes

Saunthararajah¹,

Sekeres²,

Advani³

et al. 2015

J. Clin. Invest.

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IntroductionAlthough conventional cytotoxic treatments for myeloid cancers can have differing proximal actions, e.g., topoisomerase inhibition (daunorubicin) or termination of DNA chain synthesis (cytarabine), a final common pathway converges onto p53 (TP53), a master regulator of apoptosis (cytotoxicity) (reviewed in ref. 1). As such, TP53 mutation or deletion is associated with resistance to cytotoxic treatments in vitro (2, 3) and in vivo: TP53-mutated acute myeloid leukemia (AML) treated with daunorubicin and/ or cytarabine had a response rate of 33% compared with 81% for TP53 WT AML, while TP53-mutated myelodysplastic syndromes (MDS) had a response rate of 8% versus 60% for MDS with WT TP53 (4). The poorest-risk MDS and AML subtypes, e.g., MDS and AML with complex cytogenetic abnormalities, have the highest rate of TP53 mutations, exceeding 70% in some series (5). Even if TP53 itself is not mutated, alterations in other key p53-system BACKGROUND. Mutational inactivation in cancer of key apoptotic pathway components, such as TP53/p53, undermines cytotoxic therapies that aim to increase apoptosis. Accordingly, TP53 mutations are reproducibly associated with poor treatment outcomes. Moreover, cytotoxic treatments destroy normal stem cells with intact p53 systems, a problem especially for myeloid neoplasms, as these cells reverse the low blood counts that cause morbidity and death. Preclinical studies suggest that noncytotoxic concentrations of the DNA methyltransferase 1 (DNMT1) inhibitor decitabine produce p53-independent cellcycle exits by reversing aberrant epigenetic repression of proliferation-terminating (MYC-antagonizing) differentiation genes in cancer cells. METHODS.In this clinical trial, patients with myelodysplastic syndrome (n = 25) received reduced decitabine dosages (0.1-0.2 mg/kg/day compared with the FDA-approved 20-45 mg/m 2 /day dosage, a 75%-90% reduction) to avoid cytotoxicity. These well-tolerated doses were frequently administered 1-3 days per week, instead of pulse cycled for 3 to 5 days over a 4-to 6-week period, to increase the probability that cancer S-phase entries would coincide with drug exposure, which is required for S-phase-dependent DNMT1 depletion. RESULTS.The median subject age was 73 years (range, 46-85 years), 9 subjects had relapsed disease or were refractory to 5-azacytidine and/or lenalidomide, and 3 had received intensive chemoradiation to treat other cancers. Adverse events were related to neutropenia present at baseline: neutropenic fever (13 of 25 subjects) and septic death (1 of 25 subjects). Blood count improvements meeting the International Working Group criteria for response occurred in 11 of 25 (44%) subjects and were highly durable. Treatment-induced freedom from transfusion lasted a median of 1,025 days (range, 186-1,152 days; 3 ongoing), and 20% of subjects were treated for more than 3 years. Mutations and/or deletions of key apoptosis genes were frequent (present in 55% of responders and in 36% of nonresponders). Noncytotoxic DNMT1 depletion was confirmed b...

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Section: Methodsmentioning

confidence: 99%

Evaluation of noncytotoxic DNMT1-depleting therapy in patients with myelodysplastic syndromes

Saunthararajah¹,

Sekeres²,

Advani³

et al. 2015

J. Clin. Invest.

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“…Forked DNA substrates containing DPCs for helicase assays (Fig. 1B) were constructed using methods similar to those described previously (13,17,(43)(44)(45). Briefly, a 25-mer oligonucleotide containing oxanine was ligated enzymatically with dT 60 or dT 40 using a scaffold DNA.…”

Section: Methodsmentioning

confidence: 99%

Translocation and Stability of Replicative DNA Helicases upon Encountering DNA-Protein Cross-links

Nakano

Miyamoto-Matsubara

Shoulkamy

et al. 2013

Journal of Biological Chemistry

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Background: DNA-protein cross-links (DPCs) are formed by DNA-damaging agents. Results: DPCs on the translocating strand but not on the nontranslocating strand block hexameric replicative helicases in a size-dependent manner. Stalled helicases dissociate from DNA with a half-life of 15-36 min. Conclusion: DPCs on the translocating and nontranslocating strands constitute helicase and polymerase blocks, respectively. Significance: Reversible and irreversible protein roadblocks may have distinct effects on replisomes.

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“…The pathways required to repair DNA damage from formaldehyde and acetaldehye are qualitatively similar to pathways required to repair damage from mitomycin C. Mitomycin C is a known DNA crosslinking agent that has become a functional test for activity of pathways involving Fanconi proteins and including BRCA1/2 proteins [Marietta et al (2009) (2004), Nojima et al (2005) [Nakano et al (2009[Nakano et al ( , 2003]. In mice exposed to 6 ppm formaldehyde for 1 week, the Brca pathway is among the top 10 most significantly enriched pathways [Andersen et al (2010)].…”

Section: Resultsmentioning

confidence: 99%

Preventing hereditary cancers caused by opportunistic carcinogens

Friedenson¹

2011

Nat Prec

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ObjectivesPrevious studies reported inherited BRCA1/2 deficits can cause cancer by impairing normal protective responses. Opportunistic carcinogens can exploit these deficits by causing chronic inflammation, constant cell death and replacement in a mutagenic environment, DNA crosslinking or double strand breaks. Some of the resulting cancers may be prevented if opportunistic carcinogens are identified. MethodsThe literature was systematically searched for carcinogens capable of exploiting deficits in BRCA1/2 pathways. Search criteria were common exposure, available information, required BRCA1/2 pathway repairs, increased risks for any cancer, and effects on stem cells. ResultsFormaldehyde and acetaldehyde are closely related carcinogens and common pollutants that seem everywhere. Alcohol metabolism also produces acetaldehyde. High levels of either carcinogen overwhelm normal detoxification systems, cause inflammation, inhibit DNA repair and produce DNA cross links as critical carcinogenic lesions. Searching model system studies revealed both carcinogens activate stem cells, BRCA1/2 pathways and connected BRCA1/2 pathways to myeloid leukemia. For example, the BRCA1-BARD1 complex is required for proper nucleophosmin functions. Nucleophosmin prevents a major subset of acute myeloid leukemia (AML). Next, these concepts were independently tested against risks for myeloid leukemia. Epidemiologic results showed that BRCA2 gene defects inherited on both chromosomes increased risks so dramatically that AML occurs in most children. Using data from 14 studies, known/potential heterozygous BRCA1/BRCA2 mutations increased risks for myeloid leukemias by at least 3 fold in 7 studies and by at least 50% in 12.Acetaldehyde occurs in breast milk. In model studies, excessive acetaldehyde/alcohol exposure affects estrogen metabolism and stimulates alternate alcohol detoxification pathways. These pathways can also cause DNA cross linking by releasing oxygen species and activating procarcinogens. Acetaldehyde in rats' drinking water increased incidence of leukemias, lymphomas, pancreatic tumors and fibroadenomas. Six human epidemiologic studies support an association between alcohol related genotype or alcohol consumption and early onset breast cancers, including those in BRCA1/2 mutation carriers. ConclusionsAlthough it is difficult to prove direct causation, BRCA1/2 mutation carriers may reduce cancer risks by avoiding excessive formaldehyde and acetaldehyde. Broader genetic testing and pharmacologic/nutritional detoxification are possible.

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Homologous Recombination but Not Nucleotide Excision Repair Plays a Pivotal Role in Tolerance of DNA-Protein Cross-links in Mammalian Cells

Cited by 118 publications

References 42 publications

Evaluation of noncytotoxic DNMT1-depleting therapy in patients with myelodysplastic syndromes

Evaluation of noncytotoxic DNMT1-depleting therapy in patients with myelodysplastic syndromes

Translocation and Stability of Replicative DNA Helicases upon Encountering DNA-Protein Cross-links

Preventing hereditary cancers caused by opportunistic carcinogens

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