Niacin deficiency delays DNA excision repair and increases spontaneous and nitrosourea-induced chromosomal instability in rat bone marrow

Kostecki, Lisa M.; Thomas, Megan; Linford, Geordie; Lizotte, Matthew; Toxopeus, L.; Bartleman, Anne-Pascale; Kirkland, James B.

doi:10.1016/j.mrfmmm.2007.05.008

Cited by 19 publications

(21 citation statements)

References 51 publications

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“…Consistent with the idea that catalytically-inactive PARP-1 can remain bound to strand breaks and block repair, niacin deficiency delayed the excision repair of ethyl adducts in rat bone morrow [39]. Delayed excision repair coincided with an accumulation of double strand breaks.…”

Section: Bone Marrowsupporting

confidence: 66%

“…In the mild model, with a 20% depression in NAD + , there was no increase in micronuclei. The intermediate model displayed a 50% depression in NAD + , and a doubling of micronuclei, while the severe model had an 80% depression in NAD + , and a 5-fold elevation in micronuclei [39]. The intermediate model did not display clinical signs of pellagra, and suggests that there is potential for genomic instability with subclinical deficiencies of niacin.…”

Section: Bone Marrowmentioning

confidence: 90%

“…Delayed excision repair coincided with an accumulation of double strand breaks. Even in the absence of exposure to genotoxic stress, niacin deficient bone marrow cells had dramatic increases in micronuclei, sister chromatid exchanges and chromosome breaks [39,40]. Niacin deficiency also changed p53 expression and impaired cell cycle arrest and apoptosis [41].…”

Section: Bone Marrowmentioning

confidence: 99%

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Niacin requirements for genomic stability

Kirkland

2012

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Through its involvement in over 400 NAD(P)-dependent reactions, niacin status has the potential to influence every area of metabolism. Niacin deficiency has been linked to genomic instability largely through impaired function of the poly ADP-ribose polymerase (PARP) family of enzymes. In various models, niacin deficiency has been found to cause impaired cell cycle arrest and apoptosis, delayed DNA excision repair, accumulation of single and double strand breaks, chromosomal breakage, telomere erosion and cancer development. Rat models suggest that most aspects of genomic instability are minimized by the recommended levels of niacin found in AIN-93 formulations; however, some beneficial responses do occur in the range from adequate up to pharmacological niacin intakes. Mouse models show a wide range of protection against UV-induced skin cancer well into pharmacological levels of niacin intake. It is currently a challenge to compare animal and human data to estimate the role of niacin status in the risk of genomic instability in human populations. It seems fairly certain that some portion of even affluent populations will benefit from niacin supplementation, and some subpopulations are likely well below an optimal intake of this vitamin. With exposure to stressors, like chemotherapy or excess sunlight, suraphysiological doses of niacin may be beneficial.

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Section: Bone Marrowsupporting

confidence: 66%

Section: Bone Marrowmentioning

confidence: 90%

Section: Bone Marrowmentioning

confidence: 99%

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Niacin requirements for genomic stability

Kirkland

2012

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…Double strand breaks can be measured using the neutral comet assay. Neutral MTM was nearly doubled in niacin deficient bone marrow cells 24 hours following ENU treatment, indicating an accumulation of double strand breaks (42). PARP-1 has been shown to be required for efficient resolution of stalled replication forks (44).…”

Section: Molecular Cancer Therapeuticsmentioning

confidence: 99%

“…Sister chromatid exchanges are homologous recombination events that seem to reflect the risk of nonhomologous events, and niacin deficiency increased these threefold (48). The micronucleus assay is sensitive to both DNA damage and chromosome sorting, and these lesions were increased sixfold by niacin deficiency (42).…”

Section: Molecular Cancer Therapeuticsmentioning

confidence: 99%

Niacin status and treatment-related leukemogenesis

Kirkland

2009

Molecular Cancer Therapeutics

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Chemotherapy often causes damage to hematopoietic tissues, leading to acute bone marrow suppression and the long term development of leukemias. Niacin deficiency, which is common in cancer patients, causes dramatic genomic instability in bone marrow cells in an in vivo rat model. From a mechanistic perspective, niacin deficiency delays excision repair and causes double strand break accumulation, which in turn favors chromosome breaks and translocations. Niacin deficiency also impairs cell cycle arrest and apoptosis in response to DNA damage, which combine to encourage the survival of cells with leukemogenic potential. Conversely, pharmacological supplementation of rats with niacin increases bone marrow poly (ADP-ribose) formation and apoptosis. Improvement of niacin status in rats significantly decreased nitrosoureainduced leukemia incidence. The data from our rat model suggest that niacin supplementation of cancer patients may decrease the severity of short-and long-term side effects of chemotherapy, and could improve tumor cell killing through activation of poly(ADP-ribose)-dependent apoptosis pathways. [Mol Cancer Ther 2009;8(4):725-32] Nutritional Status and Response to ChemotherapyThe successful use of chemotherapy is usually a fine balance between effective killing of tumor cells and acceptable levels of damage to normal tissues. For many types of drugs, acute bone marrow suppression may limit the dosage of chemotherapy, and DNA damage in hematopoietic cells leads to the long term development of secondary leukemias. As the success in treating childhood cancers has improved, long term cohorts have been established to monitor the late effects of cancer and chemotherapy (1-3). These studies have found roughly a 10-fold excess in risk of mortality subsequent to 5-year survival. The main cause of mortality at this stage continues to be recurrence of the original disease, reinforcing the need for treatment efficacy, but there is a significant proportion of secondary malignancies. Following 15 years of survival, there is still a fivefold excess in mortality, and secondary malignancies become the single greatest cause of death. Secondary malignancies tend to be acute myeloid leukemias, with specific presentations and genetic aberrations associated with topoisomerase inhibitors, alkylating agents, and anthracyclines (4). Radiotherapy for cancer and benign diseases also causes increased leukemia risk (5).Nutritional status in a healthy child may erode rapidly with the onset of cancer followed by chemotherapy treatment, which tends to cause nausea and gastrointestinal dysfunction (6). Malnutrition is very common and underdiagnosed at the point of diagnosis of childhood cancers (7). Nutritional status is multifactorial and likely to have impacts on both treatment efficacy and the occurrence of side effects. This area has lacked the research commitment required to characterize the effects of different nutrients, forms of cancer, and treatment regimens. The research tends to focus on broad scale nutritional ...

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