Cockayne syndrome group B protein prevents the accumulation of damaged mitochondria by promoting mitochondrial autophagy

Scheibye‐Knudsen, Morten; Ramamoorthy, Mahesh; Sýkora, Peter; Maynard, Scott; Lin, Ping Chang; Minor, Robin K.; Wilson, David M.; Cooper, Marcus P.; Spencer, Richard G.; Cabo, Rafael de; Croteau, Deborah L.; Bohr, Vilhelm A.

doi:10.1083/jcb1972oia4

Cited by 39 publications

(68 citation statements)

References 41 publications

(46 reference statements)

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“…Serum metabolic markers and intestinal tissue were normal and lipid malabsorption could be excluded. Instead, aged Csb m/m mice showed increased food consumption as well as increased O 2 consumption and CO 2 production indicative of increased metabolism (Scheibye-Knudsen et al, 2012). Together the data point to an age-related abnormality in fat tissue in Csb m/m mice, which could explain reduced body weight, and is compatible with loss of fat tissue and cachectic dwarfism in CS patients.…”

Section: Reduced Weight and Fat Tissue In Aged Csb M/m Micementioning

confidence: 92%

“…In this study the amount of body fat also was examined with T1-weighted MRI, showing reduced amounts of fat in all fat compartments with 18% and more than 60% reduction of total body fat volume at 2 and 20 months, respectively (ScheibyeKnudsen et al, 2012). Csb m/m mice were also found to show mildly reduced weight of the liver, kidney, heart and the brain in the absence of obvious histological changes, except for reduced vacuolization of aged liver cells which was interpreted as a decrease in liver lipids (Scheibye-Knudsen et al, 2012). Serum metabolic markers and intestinal tissue were normal and lipid malabsorption could be excluded.…”

Section: Reduced Weight and Fat Tissue In Aged Csb M/m Micementioning

confidence: 94%

“…Other mouse lines that may develop CS features include Xpb, Xpd, and Xpg mutant mice that carry specific XP/CS mutations (Table 1). These CS and XP/CS mice mostly show normal survival, but develop mild CS symptoms including reduced subcutaneous fat (Kamenisch et al, 2010;Scheibye-Knudsen et al, 2012), resulting in slightly reduced body weight (van der Horst et al, 1997) and mild but characteristic nervous system degenerative changes ). An additional feature of these mild CS and XP/CS mice is that they develop a severe XP/CS or COFS like phenotype when intercrossed with completely NER-deficient Xpa À/À or GG-NER-deficient Xpc À/À mice (Table 1) .…”

Section: >2 Years Unalteredmentioning

confidence: 98%

“…The second hypothesis implicates CSB in autophagic clearance of damaged and malfunctioning mitochondria. In this scenario, CSB deficiency results in accumulation of damaged mitochondria and inefficient energy metabolism (Scheibye-Knudsen et al, 2012). However, a role of CSB in mitochondria is still uncertain and alternative mechanisms underlying reduced fat tissue in Csb m/m mice cannot be excluded.…”

Section: Reduced Weight and Fat Tissue In Aged Csb M/m Micementioning

confidence: 99%

“…The term transcription-coupled repair (TCR) has been used to incorporate these broader, yet poorly defined XPA and UVSSA-independent protective activities (Hanawalt and Spivak, 2008;Hoeijmakers, 2009). In addition, it has been proposed that CS symptoms may follow from DNA damage in mitochondria (Kamenisch et al, 2010;Scheibye-Knudsen et al, 2012), or from transcriptional abnormalities independent of, or in complement to DNA repair deficits (Nouspikel, 2008).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Cockayne syndrome pathogenesis: Lessons from mouse models

Jaarsma

Pluijm

Horst

et al. 2013

Mechanisms of Ageing and Development

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Section: Reduced Weight and Fat Tissue In Aged Csb M/m Micementioning

confidence: 92%

Section: Reduced Weight and Fat Tissue In Aged Csb M/m Micementioning

confidence: 94%

Section: >2 Years Unalteredmentioning

confidence: 98%

Section: Reduced Weight and Fat Tissue In Aged Csb M/m Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Cockayne syndrome pathogenesis: Lessons from mouse models

Jaarsma

Pluijm

Horst

et al. 2013

Mechanisms of Ageing and Development

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Novel missense mutations in a conserved loop between ERCC6 (CSB) helicase motifs V and VI: Insights into Cockayne syndrome

Wilson

Lochan

Stark

et al. 2016

American J of Med Genetics Pt A

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Cockayne syndrome is caused by biallelic ERCC8 (CSA) or ERCC6 (CSB) mutations and is characterized by growth restriction, microcephaly, developmental delay, and premature pathological aging. Typically affected patients also have dermal photosensitivity. Although Cockayne syndrome is considered a DNA repair disorder, patients with UV-sensitive syndrome, with ERCC8 (CSA) or ERCC6 (CSB) mutations have indistinguishable DNA repair defects, but none of the extradermal features of Cockayne syndrome. We report novel missense mutations affecting a conserved loop in the ERCC6 (CSB) protein, associated with the Cockayne syndrome phenotype. Indeed, the amino acid sequence of this loop is more highly conserved than the adjacent helicase motifs V and VI, suggesting that this is a crucial structural component of the SWI/SNF family of proteins, to which ERCC6 (CSB) belongs. These comprise two RecA-like domains, separated by an interdomain linker, which interact through helicase motif VI. As the observed mutations are likely to act through destabilizing the tertiary protein structure, this prompted us to re-evaluate ERCC6 (CSB) mutation data in relation to the structure of SWI/SNF proteins. Our analysis suggests that antimorphic mutations cause Cockayne syndrome and that biallelic interdomain linker deletions produce more severe phenotypes. Based on our observations, we propose that further investigation of the pathogenic mechanisms underlying Cockayne syndrome should focus on the effect of antimorphic rather than null ERCC6 (CSB) mutations.

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Role of mitochondrial dysfunction in the pathophysiology of DNA repair disorders

Mori

Souza-Pinto

2018

Cell Biology International

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DNA is constantly being damaged, either by endogenous or exogenous genotoxins. In that regard, DNA repair activities are essential for maintaining genomic stability and to life itself. Mutations in genes encoding DNA repair proteins cause severe human syndromes, but DNA repair defects have also been linked to several other diseases, notably to cancer and normal aging. Recently, new evidence has emerged indicating that some DNA repair diseases display mitochondrial and metabolic dysfunction through mechanisms that are yet being uncovered. These results suggest that mitochondria play an import role in the DNA damage response pathways and that damage accumulation may lead to mitochondrial dysfunction via metabolic imbalance and mitophagy impairment. Here we review the recent findings linking mitochondrial impairment and cell death to DNA damage accumulation in the context of DNA repair defects. In addition, the general involvement of DNA damage in cellular dysfunction suggests that these phenomena may be also involved in other human pathologies in which mitochondrial dysfunction and metabolic disruption play causative roles.

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Cockayne syndrome group B protein prevents the accumulation of damaged mitochondria by promoting mitochondrial autophagy

Cited by 39 publications

References 41 publications

Cockayne syndrome pathogenesis: Lessons from mouse models

Cockayne syndrome pathogenesis: Lessons from mouse models

Novel missense mutations in a conserved loop between ERCC6 (CSB) helicase motifs V and VI: Insights into Cockayne syndrome

Role of mitochondrial dysfunction in the pathophysiology of DNA repair disorders

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