Xeroderma pigmentosum neurological abnormalities correlate with colony-forming ability after ultraviolet radiation.

Andrews, Alan D.; Barrett, Susanna F.; Robbins, Jay H.

doi:10.1073/pnas.75.4.1984

Cited by 214 publications

(73 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3 illustrates what we will refer to as the accumulated DNA damage mechanism for neurodegeneration due to DNA repair deficiency. This mechanism was originally proposed by Robbins and co-workers to explain the neurodegeneration observed in XP patients [24]. According to this mechanism, in normal individuals endogenous DNA damage is constantly being produced but also repaired, resulting in a low-steady-state level of damage which is compatible with normal cellular function.…”

Section: Caveatsmentioning

confidence: 89%

See 1 more Smart Citation

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

2008

View full text Add to dashboard Cite

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.

show abstract

Section: Caveatsmentioning

confidence: 89%

“…However, it is worth noting that at the time the mechanism [24] was originally proposed, it was very controversial and not at all well received (J. Robbins, personal communication) in part because at the time there was much less knowledge of the magnitude of endogenous DNA damage than today.…”

Section: Caveatsmentioning

confidence: 99%

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

2008

View full text Add to dashboard Cite

show abstract

“…Robbins and colleagues (Andrews et al, 1978) compared the relative survival of cells from different XP patients with or without XP neurological disease to different doses of UVradiation. These authors observed a strong correlation between reduced cell survival after UV and the severity of XP neurological disease.…”

Section: Xp Neurological Disease Results From Defective Ner Repairmentioning

confidence: 99%

“…The focus of this manuscript is to discuss the neurological disease in patients with xeroderma pigmentosum (XP), the first example of a neurological disease associated with defective DNA repair (Andrews et al, 1978). I will first review the clinical and neuropathological characteristics of XP neurological disease, as well as the evidence that it results from defective nucleotide excision repair (NER).…”

Section: Introductionmentioning

confidence: 99%

The case for 8,5′-cyclopurine-2′-deoxynucleosides as endogenous DNA lesions that cause neurodegeneration in xeroderma pigmentosum

Brooks

2007

Neuroscience

112

View full text Add to dashboard Cite

Patients with the genetic disease xeroderma pigmentosum (XP) lack the capacity to carry out a specific type of DNA repair process called nucleotide excision repair (NER). The NER pathway plays a critical role in the repair of DNA damage resulting from UV radiation. A subset of XP patients develop a profound neurodegenerative condition known as XP neurological disease. Robbins and colleagues (PNAS 75:1984(PNAS 75: -88, 1978 hypothesized that since UV light cannot reach into the human brain, XP neurological disease results from some form of endogenous DNA damage that is normally repaired by the NER pathway. In the absence of NER, the damage accumulates, causing neuronal death by blocking transcription. In this manuscript, I consider the evidence that a particular class of oxidative DNA lesions, the 8, 5'-cyclopurine-2'-deoxynucleosides, fulfills many of the criteria expected of neurodegenerative DNA lesions in XP. Specifically, these lesions are chemically stable, endogenous DNA lesions that are repaired by the NER pathway but not by any other known process, and strongly block transcription by RNA polymerase II in cells from XP patients. A similar set of criteria might be used to evaluate other candidate DNA lesions responsible for neurological diseases resulting from defects in other DNA repair mechanisms as well.

show abstract

“…Patients in groups XP-A, -D, and -G are considered to be the most severe (12), with early-onset neurological degeneration and abnormally severe sunburn reactions, whereas XP-C is considered to be intermediate, and XP-E and variant are the least severely affected. Although in some respects this is correct, especially in conditions in which UVR protection and early diagnosis is difficult, we found that early diagnosis and rigorous UVR protection can have profound effects on clinical features.…”

Section: Discussionmentioning

confidence: 99%

Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect

Fassihi

Sethi

Fawcett

et al. 2016

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

166

202

View full text Add to dashboard Cite

Xeroderma pigmentosum (XP) is a rare DNA repair disorder characterized by increased susceptibility to UV radiation (UVR)-induced skin pigmentation, skin cancers, ocular surface disease, and, in some patients, sunburn and neurological degeneration. Genetically, it is assigned to eight complementation groups (XP-A to -G and variant). For the last 5 y, the UK national multidisciplinary XP service has provided follow-up for 89 XP patients, representing most of the XP patients in the United Kingdom. Causative mutations, DNA repair levels, and more than 60 clinical variables relating to dermatology, ophthalmology, and neurology have been measured, using scoring systems to categorize disease severity. This deep phenotyping has revealed unanticipated heterogeneity of clinical features, between and within complementation groups. Skin cancer is most common in XP-C, XP-E, and XP-V patients, previously considered to be the milder groups based on cellular analyses. These patients have normal sunburn reactions and are therefore diagnosed later and are less likely to adhere to UVR protection. XP-C patients are specifically hypersensitive to ocular damage, and XP-F and XP-G patients appear to be much less susceptible to skin cancer than other XP groups. Within XP groups, different mutations confer susceptibility or resistance to neurological damage. Our findings on this large cohort of XP patients under long-term follow-up reveal that XP is more heterogeneous than has previously been appreciated. Our data now enable provision of personalized prognostic information and management advice for each XP patient, as well as providing new insights into the functions of the XP proteins.UV radiation | nucleotide excision repair | skin cancer | ocular disease | neurodegeneration

show abstract

Xeroderma pigmentosum neurological abnormalities correlate with colony-forming ability after ultraviolet radiation.

Cited by 214 publications

References 13 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?

The case for 8,5′-cyclopurine-2′-deoxynucleosides as endogenous DNA lesions that cause neurodegeneration in xeroderma pigmentosum

Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect

Contact Info

Product

Resources

About