Malondialdehyde adducts in DNA arrest transcription by T7 RNA polymerase and mammalian RNA polymerase II

Cline, Susan D.; Riggins, James N.; Tornaletti, Silvia; Marnett, Lawrence J.; Hanawalt, Philip C.

doi:10.1073/pnas.0402252101

Cited by 66 publications

(70 citation statements)

References 40 publications

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“…Since myelin is primarily composed of lipid, oxidative stress from an inflammatory response in white matter would be expected to generate lipid peroxidation products. DNA adducts from malondialdehyde and other lipid peroxidation products have been shown to block transcription [77], and are therefore likely to be subject to TC-NER. The hallmark of CS cells is their defect in TC-NER.…”

Section: Dysmyelination and Brain Calcification In Ags And Cs Neurolomentioning

confidence: 99%

Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

2008

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The classic model for neurodegeneration due to mutations in DNA repair genes holds that DNA damage accumulates in the absence of repair, resulting in the death of neurons. This model was originally put forth to explain the dramatic loss of neurons observed in patients with xeroderma pigmentosum neurologic disease, and is likely to be valid for other neurode-generative diseases due to mutations in DNA repair genes. However, in trichiothiodystrophy (TTD), Aicardi-Goutières syndrome (AGS), and Cockayne syndrome (CS), abnormal myelin is the most prominent neuropathological feature. Myelin is synthesized by specific types of glial cells called oligodendrocytes. In this review, we focus on new studies that illustrate two disease mechanisms for myelin defects resulting from mutations in DNA repair genes, both of which are fundamentally different than the classic model described above. First, studies using the TTD mouse model indicate that TFIIH acts as a co-activator for thyroid hormone-dependent gene expression in the brain, and that a causative XPD mutation in TTD results in reduction of this co-activator function and a dysregulation of myelin-related gene expression. Second, in AGS, which is caused by mutations in either TREX1 or RNASEH2, recent evidence indicates that failure to degrade nucleic acids produced during S-phase triggers activation of the innate immune system, resulting in myelin defects and calcification of the brain. Strikingly, both myelin defects and brain calcification are both prominent features of CS neurologic disease. The similar neuropathology in CS and AGS seems unlikely to be due to the loss of a common DNA repair function, and based on the evidence in the literature, we propose that vascular abnormalities may be part of the mechanism that is common to both diseases. In summary, while the classic DNA damage accumulation model is applicable to the neuronal death due to defective DNA repair, the myelination defects and brain calcification seem to be better explained by quite different mechanisms. We discuss the implications of these different disease mechanisms for the rational development of treatments and therapies.

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Section: Dysmyelination and Brain Calcification In Ags And Cs Neurolomentioning

confidence: 99%

Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

2008

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“…Moreover, some oxidative lesions, generated at the same time as those oxidized bases repairable by BER, are in fact repaired by NER. These include the cyclopurines (Brooks, 2007) and the products of lipid peroxidation, such as malondialdehyde (Cline et al, 2004). There is also a problem with intermediates in BER such as abasic sites, since abasic sites can be oxidized and then form covalent complexes with DNA polymerase beta during attempted BER and this complex lesion would require NER for its resolution (Demple and Demott, 2002).…”

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confidence: 99%

Emerging links between premature ageing and defective DNA repair

Hanawalt¹

2008

Mechanisms of Ageing and Development

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“…A recent suggestion that RNA pol II is a universal sensor of DNA damage (Lindsey-Boltz and Sancar, 2007) blurs the distinction between TCR and global repair. The neurological symptoms of CS patients have been ascribed to defective repair in the brain of endogenous oxidative damage that blocks transcription (Kuraoka et al, 2000;Osterod et al, 2002;de Waard et al, 2003;Kyng et al, 2003;Tuo et al, 2003;Cline et al, 2004), but the more common oxidative base damages (8-oxo-G, 5-hydroxycytosine, thymine glycols) do not block transcription and are therefore not the culprits in neurodegeneration (Kathe et al, 2004). CSA and CSB cells are however different in their responses to oxidative damage, despite overlap in clinical symptoms (de Waard et al, 2004;D'Errico et al, 2007).…”

Section: Do the Human Dna Repair Deficient Diseases Delineate Specifimentioning

confidence: 99%

“…ROS generate many singly modified bases such as 7,8-dihydro-8-oxoguanine (8-oxo-G) that are substrates for base excision repair (BER) (David et al, 2007), and oxidized purine products (5′,8-purine cyclodeoxynucleosides) that require NER for their repair and block transcription (Brooks et al, 2000;Kuraoka et al, 2001). Lipid oxidation products produce malondialdehydedeoxyguanosine (M-1-dG) adducts in DNA that block transcription (Cline et al, 2004). Analysis in a cell-free system showed that although UV-induced pyrimidine dimers and single strand breaks (SSBs) were effective blocks to transcription, base damage of the kind subject to BER were not (Kathe et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Clinical implications of the basic defects in Cockayne syndrome and xeroderma pigmentosum and the DNA lesions responsible for cancer, neurodegeneration and aging

Cleaver

Revet

2008

Mechanisms of Ageing and Development

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Cancer, aging, and neurodegeneration are all associated with DNA damage and repair in complex fashions. Aging appears to be a cell and tissue-wide process linked to the insulin-dependent pathway in several DNA repair deficient disorders, especially in mice. Cancer and neurodegeneration appear to have complementary relationships to DNA damage and repair. Cancer arises from surviving cells, or even stem cells, that have down-regulated many pathways, including apoptosis, that regulate genomic stability in a multi-step process. Neurodegeneration however occurs in nondividing neurones in which the persistence of apoptosis in response to reactive oxygen species is, itself, pathological. Questions that remain open concern: sources and chemical nature of naturally occurring DNA damaging agents, especially whether mitochondria are the true source; the target tissues for DNA damage and repair; do the human DNA repair deficient diseases delineate specific pathways of DNA damage relevant to clinical outcomes; if naturally occurring reactive oxygen species are pathological in human repair deficient disease, would anti-oxidants or anti-apoptotic agents be feasible therapeutic agent?

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Malondialdehyde adducts in DNA arrest transcription by T7 RNA polymerase and mammalian RNA polymerase II

Cited by 66 publications

References 40 publications

Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

Emerging links between premature ageing and defective DNA repair

Clinical implications of the basic defects in Cockayne syndrome and xeroderma pigmentosum and the DNA lesions responsible for cancer, neurodegeneration and aging

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