Article
Genetics & Heredity
Khouloud Zayoud, Ichraf Kraoua, Asma Chikhaoui, Nadege Calmels, Sami Bouchoucha, Cathy Obringer, Clement Crochemore, Dorra Najjar, Sinda Zarrouk, Najoua Miladi, Vincent Laugel, Miria Ricchetti, Ilhem Turki, Houda Yacoub-Youssef
Summary: This study investigated three patients with mutations in ERCC6/CSB, showing clinical, genetic, and functional analyses.The patients shared the same homozygous mutation, but displayed heterogeneous clinical spectrum. Patient-derived fibroblasts showed impaired NER function.
Article
Genetics & Heredity
Xinyi Wang, Yue Li, Anqi Zhao, Yumeng Wang, Qiaoyu Cao, Chaolan Pan, Ming Li
Summary: We report a case of a 3-year-old girl with photosensitivity, gait abnormalities, growth retardation, and microcephaly. The atypical clinical classification was due to mild symptoms at an early age. Next-generation sequencing identified a frameshift mutation and a novel microdeletion of the ERCC8 gene. Therefore, next-generation sequencing is essential for diagnosing and providing accurate genetic counseling for CS patients with atypical clinical manifestations.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2023)
Article
Clinical Neurology
Seth A. Stafki, Johnnie Turner, Hannah R. Littel, Christine C. Bruels, Don Truong, Ursula Knirsch, Georg M. Stettner, Urs Graf, Wolfgang Berger, Maria Kinali, Heinz Jungbluth, Christina A. Pacak, Jayne Hughes, Amytice Mirchi, Alexa Derksen, Catherine Vincent-Delorme, Arjan F. Theil, Genevieve Bernard, David Ellis, Hiva Fassihi, Alan R. Lehmann, Vincent Laugel, Shehla Mohammed, Peter B. Kang
Summary: Research has found that pathogenic variants in the MORC2 gene are associated with phenotypic similarities to Cockayne syndrome (CS) and accelerated aging features. Unlike traditional DNA repair disorders, MORC2-related disorders are not associated with a defect in transcription-coupled nucleotide excision repair and follow a dominant pattern of inheritance, with variants typically arising de novo. The results suggest that MORC2 should be included in diagnostic genetic test panels for evaluating microcephaly and/or suspected DNA repair disorders.
PEDIATRIC NEUROLOGY
(2023)
Review
Dermatology
Mansoor Hussain, Sudarshan Krishnamurthy, Jaimin Patel, Edward Kim, Beverly A. Baptiste, Deborah L. Croteau, Vilhelm A. Bohr
Summary: Defects in DNA repair pathways and mitochondrial energy metabolism can lead to various skin disorders, including rashes and pigmentation abnormalities. Accumulation of oxidative DNA damage and dysfunctional mitochondria disrupt cellular homeostasis, increasing apoptosis. Genetic disorders of premature aging affecting DNA repair pathways and causing mitochondrial dysfunction, such as Rothmund-Thomson syndrome, Werner syndrome, and Cockayne syndrome, are also associated with skin diseases. Recent research has provided insight into the molecular mechanisms underlying these syndromes and their skin pathologies.
JOURNAL OF INVESTIGATIVE DERMATOLOGY
(2021)
Article
Cell Biology
Nguyen Thuy Duong, Tran Huu Dinh, Britta S. Moehl, Stefan Hintze, Do Hai Quynh, Duong Thi Thu Ha, Ngo Diem Ngoc, Vu Chi Dung, Noriko Miyake, Nong Van Hai, Naomichi Matsumoto, Peter Meinke
Summary: This study describes siblings with classical Cockayne syndrome but without photosensitivity, leading to a delayed diagnosis. Two novel compound heterozygous ERCC8 variants were identified and their causality was confirmed through experimental investigation. Structural modeling of one variant suggests an impact on protein-protein interaction.
Editorial Material
Cell Biology
Irene Franco, Gwladys Revechon, Maria Eriksson
Summary: The causal effects of somatic mutations in the aging process are still not clear due to technological and methodological weaknesses. Studying somatic mutagenesis in different experimental systems can help understand its functional role.
Review
Biochemistry & Molecular Biology
Xiaohua Xu, Chou-Wei Chang, Min Li, Chao Liu, Yilun Liu
Summary: The RECQ4 gene encodes an ATP-dependent DNA helicase in human cells, mutations of which are linked to various clinical diseases and high cancer risks. Understanding the molecular dysfunctions of different RECQ4 disease mutations is crucial for improving our knowledge of RECQ4 clinical phenotypes and its roles in cancer development.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Article
Cell Biology
Jamie Lee, Joshua Zhang, Maeve Flanagan, Julian A. Martinez, Christopher Cunniff, Nicole Kucine, Ake T. Lu, Amin Haghani, Juozas Gordevicius, Steve Horvath, Vivian Y. Chang
Summary: Bloom syndrome (BSyn) is caused by variants in the BLM gene and manifests as poor growth, sun sensitivity, mild immunodeficiency, diabetes, and increased cancer risk, particularly leukemias. Our study reveals accelerated epigenetic aging in BSyn patients compared to carriers, as evidenced by multiple measures in blood lymphocytes. Additionally, homozygous Blm mice exhibit accelerated methylation age in various tissues according to the brain methylation clock. Overall, Bloom syndrome is associated with accelerated epigenetic aging effects in multiple tissues and significant impact on CpG methylation levels.
Review
Cell Biology
Mansour Akbari, Daryl P. Shanley, Vilhelm A. Bohr, Lene Juel Rasmussen
Summary: Aging is caused by lifelong accumulation of random damage to cells and tissues, leading to increased innate immunity markers and low-grade chronic inflammation. Activation of the DNA sensing cGAS-STING signaling pathway by misplaced cytosolic self-DNA may result in chronic inflammation and characteristics of the aging process.
Article
Cell Biology
Michela Murdocca, Paola Spitalieri, Maria Rosaria D'Apice, Giuseppe Novelli, Federica Sangiuolo
Summary: Aging is a complex biological process closely linked to cancer and inflammation, which are the subjects of extensive research. The accumulation of DNA damage interferes with cellular function and increases susceptibility to aging conditions.
MECHANISMS OF AGEING AND DEVELOPMENT
(2023)
Review
Cell Biology
Zoi Spyropoulou, Angelos Papaspyropoulos, Nefeli Lagopati, Vassilios Myrianthopoulos, Alexandros G. Georgakilas, Maria Fousteri, Athanassios Kotsinas, Vassilis G. Gorgoulis
Summary: Cockayne syndrome is a DNA repair syndrome with symptoms like neurodegeneration and premature aging, mainly caused by mutations in the CSB gene. Besides its role in DNA repair pathways, CSB is also involved in DNA transcription, mitochondrial biology, telomere maintenance, and p53 regulation.
Article
Cell Biology
Jong-Hyuk Lee, Raghavendra A. Shamanna, Tomasz Kulikowicz, Nima Borhan Fakouri, Edward W. Kim, Louise S. Christiansen, Deborah L. Croteau, Vilhelm A. Bohr
Summary: Werner syndrome (WS) is an accelerated aging disorder characterized by genomic instability caused by WRN protein deficiency. The phosphorylation of WRN by CDK2 on serine residue 426 is critical for WRN to choose between non-homologous end joining (NHEJ) and homologous recombination (HR) pathways. The phosphorylation stabilizes WRN's affinity for RPA and enhances its role in long-range resection, a crucial step for HR.
Article
Cell Biology
Michela Murdocca, Paola Spitalieri, Angela Cappello, Fiorella Colasuonno, Sandra Moreno, Eleonora Candi, Maria Rosaria D'Apice, Giuseppe Novelli, Federica Sangiuolo
Summary: MDPL Syndrome is a rare genetic premature aging disease characterized by mandibular hypoplasia, deafness, progeroid features, and concomitant lipodystrophy. In this study, the role of mitochondrial metabolism and activity in the pathogenesis of MDPL Syndrome was investigated. The results demonstrated a significant impairment of mitochondrial biogenesis and activity in MDPL cells, accompanied by increased production of reactive oxygen species (ROS). While Metformin was unable to restore mitochondrial impairment, it showed efficacy in rescuing nuclear abnormalities associated with the premature aging phenotype.
Article
Multidisciplinary Sciences
Chunli Yan, Thomas Dodd, Jina Yu, Bernice Leung, Jun Xu, Juntaek Oh, Dong Wang, Ivaylo Ivanov
Summary: The authors provide models of RNA polymerase II bound to the yeast CSB ortholog Rad26 to explain how CSB helps the polymerase bypass DNA lesions and interpret the effects of disease mutations. They identified an allosteric pathway that links Rad26 ATPase modules to changes in RNA polymerase and DNA, revealing a structural mechanism for CSB-assisted progression past less bulky lesions. Overall, the study sheds light on the functional interpretation of Cockayne syndrome disease mutations.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Laura A. Lindsey-Boltz, Yanyan Yang, Cansu Kose, Nazli Deger, Khagani Eynullazada, Hiroaki Kawara, Aziz Sancar
Summary: Nucleotide excision repair removes UV-induced DNA damage through two sub-pathways, global repair and transcription-coupled repair. XPC is required for repair of nontranscribed DNA, while CSB is required for repair of transcribed DNA. Unexpectedly, XPC-/-/CSB-/- double mutant cell lines still exhibit transcription-coupled repair. However, mutating the CSA gene eliminates all residual transcription-coupled repair activity.
NUCLEIC ACIDS RESEARCH
(2023)