XPA deficiency affects the ubiquitin-proteasome system function

Leal, Angélica Maria de Sousa; Medeiros, Lázaro Batista de Azevedo; Muñoz-Cadavid, Cesar Orlando; Oliveira, Riva de Paula; Timóteo, Ana Rafaela de Souza; Oliveira, A.L. de; Faustino, André Luís Fonseca; Silva, Vandeclécio Lira da; Souza, Sandro J. de; Lajus, Tirzah Braz Petta; Campos, Julliane Tamara Araújo de Melo; Agnez-Lima, Lucymara Fassarella

doi:10.1016/j.dnarep.2020.102937

Cited by 6 publications

(4 citation statements)

References 74 publications

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“…ATM-1, BRC-1 and UNG-1 fulfill largely different roles in distinct DDR pathways, with entirely different functions and enzymatic activities (see also Supplemental Table 1), suggesting that the loss of protein homeostasis that we observe is not limited to any particular molecular DDR defect. This is in line with other evidence linking defects in various DDR pathways to a loss of protein homeostasis (Arczewska et al, 2013;de Sousa Leal et al, 2020;Lee et al, 2018;Talaei et al, 2013).…”

Section: Discussionsupporting

confidence: 92%

Preserving protein homeostasis prevents motor impairment in DNA Damage Response-compromised C. elegans

Huiting

Duque‐Jaramillo

Seinstra

et al. 2021

Preprint

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To maintain genome integrity, cells rely on a complex system of DNA repair pathways and cell cycle checkpoints, together referred to as the DNA damage response (DDR). Impairments in DDR pathways are linked to cancer, but also to a wide range of degenerative processes, frequently including progressive neuropathy and accelerated aging. How defects in mechanistically distinct DDR pathways can drive similar degenerative phenotypes is not understood. Here we show that defects in various DDR components are linked to a loss of protein homeostasis in Caenorhabditis elegans. Prolonged silencing of atm-1, brc-1 or ung-1, central components in respectively checkpoint signaling, double strand break repair and base excision repair enhances the global aggregation of proteins occurring in adult animals, and accelerates polyglutamine protein aggregation in a model for neurodegenerative diseases. Overexpression of the molecular chaperone HSP-16.2 prevents enhanced protein aggregation in atm-1, brc-1 or ung-1-compromised animals. Strikingly, rebalancing protein homeostasis with HSP-16.2 almost completely rescues age-associated impaired motor function in these animals as well. This reveals that the consequences of a loss of atm-1, brc-1 or ung-1 converge on an impaired protein homeostasis to cause degeneration. These findings indicate that a loss of protein homeostasis is a crucial downstream consequence of DNA repair defects, and thereby provide an attractive novel framework for understanding the broad link between DDR defects and degenerative processes.

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Section: Discussionsupporting

confidence: 92%

Preserving protein homeostasis prevents motor impairment in DNA Damage Response-compromised C. elegans

Huiting

Duque‐Jaramillo

Seinstra

et al. 2021

Preprint

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“…Since neuronal cells are not predisposed directly to the injurious effects of ultraviolet (UV) radiation, other mechanisms for neuronal injury in XP patients have been proposed [ 26 ]. One suggested mechanism may be generation of oxidative stress [ 27 ]. The reactive oxygen species (ROS) are constantly generated during aerobic metabolism.…”

Section: Discussionmentioning

confidence: 99%

Differences in peripheral neuropathy in xeroderma pigmentosum complementation groups A and D as evaluated by nerve conduction studies

et al. 2021

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Background Xeroderma pigmentosum (XP) is a rare autosomal recessive genetic disorder with defective DNA nucleotide excision repair and associated with a high frequency of skin cancer. Approximately 25% of patients develop progressive neurological degeneration. Complementation groups XP-A and XP-D are most frequently associated with neurological disorders. Design/methods This is a retrospective review of patients with XP who were evaluated at NIH from 1986 to 2015 and had nerve conduction studies (NCS). In the complementation groups with peripheral neuropathy, further comparisons of the NCS were made with audiological, brain imaging, neuropsychological assessments that were also performed on most of the patients. Limited neuropathology of XP-A and XP-D patients were examined.. Results The 33 patients had NCS: XP-A (9 patients), XP-C (7 patients), XP-D (10 patients), XP-E (1 patient), XP-V (4 patients), and XP-unknown (2 patients). Peripheral neuropathy based on nerve conduction studies was documented only in two complementation groups: 78% (7/9) of XP-A patients had a sensorimotor neuropathy while 50% (5/10) of XP-D patients had a sensory neuropathy only. Analysis of sural sensory nerve amplitude in both complementation groups XP-A and XP-D correlated with sensorineural hearing loss (SNHL), MRI/CT severity, and Full-scale Intelligence Quotient (IQ). Analysis of fibular motor nerve amplitude in complementation XP-A correlated with SNHL and MRI/CT severity. Limited follow-up studies showed gradual loss of NCS responses compared to an earlier and more rapid progression of the hearing loss. Conclusions Despite similar brain imaging and audiological findings patients, XP-A and XP-D complementation groups differ in the type of neuropathy, sensorimotor versus sensory alone. A few cases suggest that sensorineural hearing loss may precede abnormal NCS in XP and therefore serve as valuable clinical indicators of XP patients that will later develop peripheral neuropathy.

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“…This is important to facilitate the scheduled degradation of chromatin and repair factors to promote DNA repair (84). Cells from individuals carrying mutations in XPA, which is essential for NER, exhibit lower proteasome activity and accumulate protein aggregates (80), and XPA-deficient C. elegans show increased levels of polyubiquitylated proteins (85), indicating that persistent DNA damage can cause proteotoxic stress by overwhelming the UPS.…”

Section: Dna Damage Causes Proteotoxic Stressmentioning

confidence: 99%

Genome Instability and DNA Repair in Somatic and Reproductive Aging

Panier,

Wang,

Schumacher

2024

Annu. Rev. Pathol. Mech. Dis.

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Genetic material is constantly subjected to genotoxic insults and is critically dependent on DNA repair. Genome maintenance mechanisms differ in somatic and germ cells as the soma only requires maintenance during an individual's lifespan, while the germline indefinitely perpetuates its genetic information. DNA lesions are recognized and repaired by mechanistically highly diverse repair machineries. The DNA damage response impinges on a vast array of homeostatic processes and can ultimately result in cell fate changes such as apoptosis or cellular senescence. DNA damage causally contributes to the aging process and aging-associated diseases, most prominently cancer. By causing mutations, DNA damage in germ cells can lead to genetic diseases and impact the evolutionary trajectory of a species. The mechanisms ensuring tight control of germline DNA repair could be highly instructive in defining strategies for improved somatic DNA repair. They may provide future interventions to maintain health and prevent disease during aging. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 19 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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XPA deficiency affects the ubiquitin-proteasome system function

Cited by 6 publications

References 74 publications

Preserving protein homeostasis prevents motor impairment in DNA Damage Response-compromised C. elegans

Preserving protein homeostasis prevents motor impairment in DNA Damage Response-compromised C. elegans

Differences in peripheral neuropathy in xeroderma pigmentosum complementation groups A and D as evaluated by nerve conduction studies

Genome Instability and DNA Repair in Somatic and Reproductive Aging

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