Beyond DNA repair and chromosome instability—Fanconi anaemia as a cellular senescence-associated syndrome

Helbling-Leclerc, Anne; Garcin, Cecile; Rosselli, Filippo

doi:10.1038/s41418-021-00764-5

Cited by 32 publications

(24 citation statements)

References 125 publications

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“…2) while ruling out cell death by apoptosis (supplementary table 1), in accord with premature senescence. Similar to our observations, FA patients' cells demonstrated cellular features related to senescence, including decreased proliferation, a short lifespan of broblasts and increased expression of SA-β-gal [21,22]. Telomere shortening is another feature of senescence and DNA breakage and is also associated with FA, which ts well with our present ndings.…”

Section: Discussionsupporting

confidence: 91%

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Mitochondrial COX4-1 deficiency leads to impaired nuclear DNA damage response resulting in proliferation deficits and premature senescence

Douiev

Miller

Benyamini

et al. 2021

Preprint

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Cytochrome- c- oxidase (COX), a multimeric protein complex, is the final electron acceptor in the mitochondrial electron transfer chain. Primary COX deficiency, caused by mutations in either mitochondrial DNA or nuclear-encoded genes, is a heterogenous group of mitochondrial diseases with a wide range of presentations ranging from fatal infantile to subtler. We previously reported a patient with primary COX deficiency due to a pathogenic variant in COX4I1 (encoding the common isoform of COX subunit 4), who presented with bone-marrow failure, genomic instability and short stature, mimicking Fanconi anemia (FA). In the present study, we demonstrated reduced proliferation and premature senescence in this patient’s fibroblasts and in COX4-1 knockdown cells. Accumulative DNA damage coincided primarily with proliferative cells, indicating replicative stress. Expression analysis implicated DNA damage response which was verified by demonstrating impaired recovery from genotoxic insult and decreased DNA repair. Interestingly, our in-vitro findings recapitulate the patient’s presentation and present status. Thus, we suggest that the premature senescence, resulting from accumulative DNA damage in COX4-1 deficiency is a protective mechanism to avoid malignant transformation in a similar manner to what was reported for FA and other “accelerated aging diseases”.

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Section: Discussionsupporting

confidence: 91%

“…3). This is also compatible with FA pathway de cits which are characterized by accumulative DNA damage, replication crisis and chromosomal aberrations due to impaired to DNA damage response (DDR) [22]. To strengthen this hypothesis, we proceeded to examine DDR by expression analysis (Fig.…”

Section: Discussionmentioning

confidence: 61%

Mitochondrial COX4-1 deficiency leads to impaired nuclear DNA damage response resulting in proliferation deficits and premature senescence

Douiev

Miller

Benyamini

et al. 2021

Preprint

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“…TP53 is the most easily compromised gene target modulating cell behavior (189) and participates in radiation-induced digestive injury. p53 is involved in many pathways, including p38/p53/p21 (senescence related) (190), p53/Reprimo (cell cycle arrest at G2/M) (191), Gadd45/ p38/p53 (cell cycle checkpoints, apoptosis, and DNA repair), p53-FAS (apoptosis receptor in cell membrane) (192), PIDD (P53-induced protein with a death domain) (193), p53/bcl-2/Bax (apoptosis pathway) (194), p53-inducible genes (195), p53/ Scotin (cell cycle arrest, apoptosis) (196), and ATF6/p53/ AIFM2 (197).…”

Section: B) Apoptosis In Radiation-induced Digestive Injurymentioning

confidence: 99%

Radiotherapy-Induced Digestive Injury: Diagnosis, Treatment and Mechanisms

et al. 2021

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Radiotherapy is one of the main therapeutic methods for treating cancer. The digestive system consists of the gastrointestinal tract and the accessory organs of digestion (the tongue, salivary glands, pancreas, liver and gallbladder). The digestive system is easily impaired during radiotherapy, especially in thoracic and abdominal radiotherapy. In this review, we introduce the physical classification, basic pathogenesis, clinical characteristics, predictive/diagnostic factors, and possible treatment targets of radiotherapy-induced digestive injury. Radiotherapy-induced digestive injury complies with the dose-volume effect and has a radiation-based organ correlation. Computed tomography (CT), MRI (magnetic resonance imaging), ultrasound (US) and endoscopy can help diagnose and evaluate the radiation-induced lesion level. The latest treatment approaches include improvement in radiotherapy (such as shielding, hydrogel spacers and dose distribution), stem cell transplantation and drug administration. Gut microbiota modulation may become a novel approach to relieving radiogenic gastrointestinal syndrome. Finally, we summarized the possible mechanisms involved in treatment, but they remain varied. Radionuclide-labeled targeting molecules (RLTMs) are promising for more precise radiotherapy. These advances contribute to our understanding of the assessment and treatment of radiation-induced digestive injury.

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“…Genome instability (including instability at the chromosomal/subchromosomal level) seems to be involved in the normal and pathogenic aging of the human brain [8,9]. CINassociated diseases (i.e., CIN syndromes) exhibit progeroid phenotypes and/or cellular phenotypes hallmarking aging processes [10,11]. Significantly, CIN may represent a mechanism for neurodegeneration in diseases featured by accelerated aging [12].…”

Section: Introductionmentioning

confidence: 99%

Chromosome Instability, Aging and Brain Diseases

Iourov

Yurov

Vorsanova

et al. 2021

Cells

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Chromosome instability (CIN) has been repeatedly associated with aging and progeroid phenotypes. Moreover, brain-specific CIN seems to be an important element of pathogenic cascades leading to neurodegeneration in late adulthood. Alternatively, CIN and aneuploidy (chromosomal loss/gain) syndromes exhibit accelerated aging phenotypes. Molecularly, cellular senescence, which seems to be mediated by CIN and aneuploidy, is likely to contribute to brain aging in health and disease. However, there is no consensus about the occurrence of CIN in the aging brain. As a result, the role of CIN/somatic aneuploidy in normal and pathological brain aging is a matter of debate. Still, taking into account the effects of CIN on cellular homeostasis, the possibility of involvement in brain aging is highly likely. More importantly, the CIN contribution to neuronal cell death may be responsible for neurodegeneration and the aging-related deterioration of the brain. The loss of CIN-affected neurons probably underlies the contradiction between reports addressing ontogenetic changes of karyotypes within the aged brain. In future studies, the combination of single-cell visualization and whole-genome techniques with systems biology methods would certainly define the intrinsic role of CIN in the aging of the normal and diseased brain.

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Beyond DNA repair and chromosome instability—Fanconi anaemia as a cellular senescence-associated syndrome

Cited by 32 publications

References 125 publications

Mitochondrial COX4-1 deficiency leads to impaired nuclear DNA damage response resulting in proliferation deficits and premature senescence

Mitochondrial COX4-1 deficiency leads to impaired nuclear DNA damage response resulting in proliferation deficits and premature senescence

Radiotherapy-Induced Digestive Injury: Diagnosis, Treatment and Mechanisms

Chromosome Instability, Aging and Brain Diseases

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