An ever-changing landscape in Roberts syndrome biology: Implications for macromolecular damage

Mfarej, Michael G.; Skibbens, Robert V.

doi:10.1371/journal.pgen.1009219

Cited by 11 publications

(10 citation statements)

References 118 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, elevated ROS levels present in cells deficient in Esco2 and cohesin functions are likely to incur additional levels of macromolecular damage to DNA, proteins, and lipids. This model suggests that RBS cytotoxicity may arise through several synergistic ROS-dependent mechanisms that include oxidation of DNA and proteins that may contribute to defects in transcription, translation, and SCC ( Figure 5B ) (reviewed in Mfarej and Skibbens 2020b ).…”

Section: Discussionmentioning

confidence: 99%

Genetically induced redox stress occurs in a yeast model for Roberts syndrome

Mfarej

Skibbens

2021

G3 Genes|Genomes|Genetics

Self Cite

View full text Add to dashboard Cite

Roberts Syndrome (RBS) is a multi-spectrum developmental disorder characterized by severe limb, craniofacial, and organ abnormalities and often intellectual disabilities. The genetic basis of RBS is rooted in loss-of-function mutations in the essential N-acetyltransferase ESCO2 which is conserved from yeast (Eco1/Ctf7) to humans. ESCO2/Eco1 regulate many cellular processes that impact chromatin structure, chromosome transmission, gene expression, and repair of the genome. The etiology of RBS remains contentious with current models that include transcriptional dysregulation or mitotic failure. Here, we report evidence that supports an emerging model rooted in defective DNA damage responses. First, the results reveal that redox stress is elevated in both eco1 and cohesion factor Saccharomyces cerevisiae mutant cells. Second, we provide evidence that Eco1 and cohesion factors are required for the repair of oxidative DNA damage such that ECO1 and cohesin gene mutations result in reduced cell viability and hyperactivation of DNA damage checkpoints that occur in response to oxidative stress. Moreover, we show that mutation of ECO1 is solely sufficient to induce endogenous redox stress and sensitizes mutant cells to exogenous genotoxic challenges. Remarkably, antioxidant treatment desensitizes eco1 mutant cells to a range of DNA damaging agents, raising the possibility that modulating the cellular redox state may represent an important avenue of treatment for Roberts Syndrome and tumors that bear ESCO2 mutations.

show abstract

Section: Discussionmentioning

confidence: 99%

Genetically induced redox stress occurs in a yeast model for Roberts syndrome

Mfarej

Skibbens

2021

G3 Genes|Genomes|Genetics

Self Cite

View full text Add to dashboard Cite

show abstract

“…In a normal cell division, each chromosome is copied and then attached to its newly formed copy at the centromere. 16 During the cell division in Roberts syndrome, the copies are not attached at the centromere. Consequently, the chromosomes are not properly aligned with resultant slowing or no division of cells.…”

Section: Discussionmentioning

confidence: 99%

Roberts syndrome with tetraphocomelia: A case report and literature review

Okpala

Echendu²,

Ikechebelu

et al. 2022

SAGE Open Medical Case Reports

View full text Add to dashboard Cite

Roberts syndrome is a rare genetic disorder characterized by symmetrical reductive limb malformation and craniofacial abnormalities. It is caused by mutation in the “Establishment of cohesion 1 homolog 2” genes, resulting in the loss of acetyltransferase activities and manifesting as premature centromere separation in metaphase chromosomes. The affected individual grows slowly during pregnancy and after birth with associated mild to severe intellectual impairment. We present a 35-year-old multiparous Nigerian lady who had emergency cesarean section at 35 weeks of gestation following abruptio placentae with a live fetus. The baby had poor Apgar score at birth and died shortly afterward. Tetraphocomelia was detected on prenatal ultrasound done at about 24 weeks of gestation with other features sonographically normal. However, clinical diagnosis of severe variant of Roberts syndrome with tetraphocomelia, growth restriction, and craniofacial abnormalities were noted at birth. This case exhibits a very rare variant of Roberts syndrome with tetraphocomelia, intrauterine growth restriction, and craniofacial abnormalities. It also highlights the crucial role of detailed clinical examination and the inherent challenges in making cytogenetic diagnosis in low-income countries.

show abstract

“…Finally, the identification of CLN2 deletion as a suppressor of eco1 rad61 mutant cell ts growth defects provides a new framework for interpreting results from studies regarding the role of cyclins in development and cancer. In humans, severe developmental defects, collectively referred to as cohesinopathies, result from mutation of ESCO2 (homolog of yeast Eco1/Ctf7), most cohesin genes ( SMC1A , SMC3 , PDS5 , RAD21 ) or cohesin regulators ( NIPBL or HDAC8 ) (reviewed in Banerji et al 2017a ; Sarogni et al 2020 ; Mfarej and Skibbens 2020b ; Vega et al 2020 ). All of these cohesin-pathway genes are essential, such that the syndromes that arise from ESCO2 mutation (RBS) or cohesin/regulator mutations (CdLS) occur infrequently—likely due to early and spontaneous pregnancy terminations.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous studies document that cohesin-dependent chromatin looping during G1 plays a critical role in both large- and small-scale conformations. Importantly, loops produced via cohesin-based DNA extrusion can bring into registration DNA regulatory elements (enhancers, insulators, and promoters) that either induce or repress the transcription of individual genes (reviewed in Mfarej and Skibbens 2020b ; Perea-Resa et al 2021 ; Horsfield 2022 ). In this light, it is not surprising that mutations in cohesins, or cohesin regulators, result in genome-wide transcription dysregulation and severe birth defects (reviewed in Dorsett 2016 ; Banerji et al 2017a ; Deardorff et al .…”

Section: Introductionmentioning

confidence: 99%

G1-Cyclin2 (Cln2) promotes chromosome hypercondensation in eco1/ctf7 rad61 null cells during hyperthermic stress in Saccharomyces cerevisiae

Buskirk

Skibbens

2022

G3 Genes|Genomes|Genetics

Self Cite

View full text Add to dashboard Cite

Eco1/Ctf7 is a highly conserved acetyltransferase that activates cohesin complexes and is critical for sister chromatid cohesion, chromosome condensation, DNA damage repair, nucleolar integrity, and gene transcription. Mutations in the human homolog of ECO1 (ESCO2/EFO2), or in genes that encode cohesin subunits, result in severe developmental abnormalities and intellectual disabilities referred to as Roberts Syndrome (RBS) and Cornelia de Lange Syndrome (CdLS), respectively. In yeast, deletion of ECO1 results in cell inviability. Co-deletion of RAD61 (WAPL in humans), however, produces viable yeast cells. These eco1 rad61 double mutants, however, exhibit a severe temperature-sensitive growth defect, suggesting that Eco1 or cohesins respond to hyperthermic stress through a mechanism that occurs independent of Rad61. Here, we report that deletion of the G1 cyclin CLN2 rescues the temperature sensitive lethality otherwise exhibited by eco1 rad61 mutant cells, such that the triple mutant cells exhibit robust growth over a broad range of temperatures. While Cln1, Cln2 and Cln3 are functionally redundant G1 cyclins, neither CLN1 nor CLN3 deletions rescue the temperature-sensitive growth defects otherwise exhibited by eco1 rad61 double mutants. We further provide evidence that CLN2 deletion rescues hyperthermic growth defects independent of START and impacts the state of chromosome condensation. These findings reveal novel roles for Cln2 that are unique among the G1 cyclin family and appear critical for cohesin regulation during hyperthermic stress.

show abstract

An ever-changing landscape in Roberts syndrome biology: Implications for macromolecular damage

Cited by 11 publications

References 118 publications

Genetically induced redox stress occurs in a yeast model for Roberts syndrome

Genetically induced redox stress occurs in a yeast model for Roberts syndrome

Roberts syndrome with tetraphocomelia: A case report and literature review

G1-Cyclin2 (Cln2) promotes chromosome hypercondensation in eco1/ctf7 rad61 null cells during hyperthermic stress in Saccharomyces cerevisiae

Contact Info

Product

Resources

About