Abstract: Cockayne syndrome (CS) group B (CSB), which results from mutations in the excision repair cross-complementation group 6 (ERCC6) genes, which produce CSB protein, is an autosomal recessive disease characterized by multiple progressive disorders including growth failure, microcephaly, skin photosensitivity, and premature aging. Clinical data show that brain atrophy, demyelination, and calcification are the main neurological manifestations of CS, which progress with time. Neuronal loss and calcification occur in various brain areas, particularly the cerebellum and basal ganglia, resulting in dyskinesia, ataxia, and limb tremors in CSB patients. However, the understanding of neurodevelopmental defects in CS has been constrained by the lack of significant neurodevelopmental and functional abnormalities observed in CSB-deficient mice. In this review, we focus on elucidating the protein structure and distribution of CSB and delve into the impact of CSB mutations on the development and function of the nervous system. In addition, we provide an overview of research models that have been instrumental in exploring CS disorders, with a forward-looking perspective on the substantial contributions that brain organoids are poised to further advance this field.

Cockayne综合征B神经系统病变研究展望： 患者来源的脑类器官模型的应用

[1]AamannMD, SorensenMM, HvitbyC, et al., 2010. Cockayne syndrome group B protein promotes mitochondrial DNA stability by supporting the DNA repair association with the mitochondrial membrane. FASEB J, 24(7):2334-2346.

[2]AnnaA, MonikaG, 2018. Splicing mutations in human genetic disorders: examples, detection, and confirmation. J Appl Genet, 59(3):253-268.

[3]AtalayB, SorkunM, KaratoprakEY, 2021. Cockayne syndrome type: a very rare association with hemorrhagic stroke. Turk J Pediatr, 63(5):922-926.

[4]BatenburgNL, WalkerJR, NoordermeerSM, et al., 2017. ATM and CDK2 control chromatin remodeler CSB to inhibit RIF1 in DSB repair pathway choice. Nat Commun, 8:1921.

[5]BatenburgNL, WalkerJR, CoulombeY, et al., 2019. CSB interacts with BRCA1 in late S/G2 to promote MRN- and CtIP-mediated DNA end resection. Nucleic Acids Res, 47(20):10678-10692.

[6]BatenburgNL, CuiSX, WalkerJR, et al., 2021. The winged helix domain of CSB regulates RNAPII occupancy at promoter proximal pause sites. Int J Mol Sci, 22(7):3379.

[7]BiancoJN, SchumacherB, 2018. MPK-1/ERK pathway regulates DNA damage response during development through DAF-16/FOXO. Nucleic Acids Res, 46(12):6129-6139.

[8]BoetefuerEL, LakeRJ, FanHY, 2018. Mechanistic insights into the regulation of transcription and transcription-coupled DNA repair by Cockayne syndrome protein B. Nucleic Acids Res, 46(15):7471-7479.

[9]CalmelsN, BottaE, JiaN, et al., 2018. Functional and clinical relevance of novel mutations in a large cohort of patients with Cockayne syndrome. J Med Genet, 55(5):‍329-343.

[10]CaputoM, BalzeranoA, ArisiI, et al., 2017. CSB ablation induced apoptosis is mediated by increased endoplasmic reticulum stress response. PLoS ONE, 12(3):e0172399.

[11]CarrollJ, PabstL, KoboldtDC, et al., 2023. Novel presentation of hemiplegic migraine in a patient with Cockayne syndrome. Pediatr Neurol, 138:95-97.

[12]ChenY, BuryLA, ChenF, et al., 2023. Generation of advanced cerebellar organoids for neurogenesis and neuronal network development. Hum Mol Genet, 32(18):2832-2841.

[13]ChoI, TsaiPF, LakeRJ, et al., 2013. ATP-dependent chromatin remodeling by Cockayne syndrome protein B and NAP1-like histone chaperones is required for efficient transcription-coupled DNA repair. PLoS Genet, 9(4):e1003407.

[14]CiaffardiniF, NicolaiS, CaputoM, et al., 2014. The Cockayne syndrome B protein is essential for neuronal differentiation and neuritogenesis. Cell Death Dis, 5(5):e1268.

[15]CitterioE, van den BoomV, SchnitzlerG, et al., 2000. ATP-dependent chromatin remodeling by the Cockayne syndrome B DNA repair-transcription-coupling factor. Mol Cell Biol, 20(20):7643-7653.

[16]ColellaS, NardoT, BottaE, et al., 2000. Identical mutations in the CSB gene associated with either Cockayne syndrome or the DeSanctis–Cacchione variant of xeroderma pigmentosum. Hum Mol Genet, 9(8):1171-1175.

[17]Damaj-FourcadeR, MeyerN, ObringerC, et al., 2022. Statistical approach of the role of the conserved CSB-PiggyBac transposase fusion protein (CSB-PGBD3) in genotype-phenotype correlation in Cockayne syndrome type B. Front Genet, 13:762047.

[18]de Sousa AndradeLN, NathansonJL, YeoGW, et al., 2012. Evidence for premature aging due to oxidative stress in iPSCs from Cockayne syndrome. Hum Mol Genet, 21(17):3825-3834.

[19]EngleSJ, BlahaL, KleimanRJ, 2018. Best practices for translational disease modeling using human iPSC-derived neurons. Neuron, 100(4):783-797.

[20]EpanchintsevA, CostanzoF, RauschendorfMA, et al., 2017. Cockayne’s syndrome A and B proteins regulate transcription arrest after genotoxic stress by promoting ATF3 degradation. Mol Cell, 68(6):1054-1066.e6.

[21]FangG, BhardwajN, RobilottoR, et al., 2010. Getting started in gene orthology and functional analysis. PLoS Comput Biol, 6(3):e1000703.

[22]GrayLT, FongKK, PavelitzT, et al., 2012. Tethering of the conserved piggyBac transposase fusion protein CSB-PGBD3 to chromosomal AP-1 proteins regulates expression of nearby genes in humans. PLoS Genet, 8(9):e1002972.

[23]International Human Genome Sequencing Consortium, 2001. Initial sequencing and analysis of the human genome. Nature, 409(6822):860-921.

[24]IshidaY, KawakamiH, KitajimaH, et al., 2016. Vulnerability of Purkinje cells generated from spinocerebellar ataxia type 6 patient-derived iPSCs. Cell Rep, 17(6):1482-1490.

[25]LakeRJ, FanHY, 2013. Structure, function and regulation of CSB: a multi-talented gymnast. Mech Ageing Dev, 134(5-6):202-211.

[26]IyamaT, WilsonDM III, 2016. Elements that regulate the DNA damage response of proteins defective in Cockayne syndrome. J Mol Biol, 428(1):62-78.

[27]IyamaT, OkurMN, GolatoT, et al., 2018. Regulation of the intranuclear distribution of the Cockayne syndrome proteins. Sci Rep, 8:17490.

[28]JaarsmaD, van der PluijmI, van der HorstGTJ, et al., 2013. Cockayne syndrome pathogenesis: lessons from mouse models. Mech Ageing Dev, 134(5-6):180-195.

[29]KamenischY, BerneburgM, 2013. Mitochondrial CSA and CSB: protein interactions and protection from ageing associated DNA mutations. Mech Ageing Dev, 134(5-6):270-274.

[30]KarikkinethAC, Scheibye-KnudsenM, FivensonE, et al., 2017. Cockayne syndrome: clinical features, model systems and pathways. Ageing Res Rev, 33:3-17.

[31]KawajiH, KasukawaT, ForrestA, et al., 2017. The FANTOM5 collection, a data series underpinning mammalian transcriptome atlases in diverse cell types. Sci Data, 4:170113.

[32]KokicG, WagnerFR, ChernevA, et al., 2021. Structural basis of human transcription-DNA repair coupling. Nature, 598(7880):368-372.

[33]KoobM, LaugelV, DurandM, et al., 2010. Neuroimaging in Cockayne syndrome. Am J Neuroradiol, 31(9):1623-1630.

[34]KyngKJ, MayA, BroshRMJr, et al., 2003. The transcriptional response after oxidative stress is defective in Cockayne syndrome group B cells. Oncogene, 22(8):1135-1149.

[35]LaposaRR, HuangEJ, CleaverJE, 2007. Increased apoptosis, p53 up-regulation, and cerebellar neuronal degeneration in repair-deficient Cockayne syndrome mice. Proc Natl Acad Sci USA, 104(4):1389-1394.

[36]LatiniP, FrontiniM, CaputoM, et al., 2011. CSA and CSB proteins interact with p53 and regulate its Mdm2-dependent ubiquitination. Cell Cycle, 10(21):3719-3730.

[37]LaugelV, 2013. Cockayne syndrome: the expanding clinical and mutational spectrum. Mech Ageing Dev, 134(5-6):161-170.

[38]LeeMH, AhnB, ChoiIS, et al., 2002. The gene expression and deficiency phenotypes of Cockayne syndrome B protein in Caenorhabditis elegans. FEBS Lett, 522(1-3):‍47-51.

[39]LiYQ, WongCS, 2018. Effects of p21 on adult hippocampal neuronal development after irradiation. Cell Death Discov, 4:79.

[40]LiangFK, LiBJ, XuYY, et al., 2023. Identification and characterization of Necdin as a target for the Cockayne syndrome B protein in promoting neuronal differentiation and maintenance. Pharmacol Res, 187:106637.

[41]LopesAFC, BozekK, HerholzM, et al., 2020. A C. elegans model for neurodegeneration in Cockayne syndrome. Nucleic Acids Res, 48(19):10973-10985.

[42]LuKQ, HongY, TaoMD, et al., 2023. Depressive patient-derived GABA interneurons reveal abnormal neural activity associated with HTR2C. EMBO Mol Med, 15:e16364.

[43]Maor-NofM, ShiponyZ, Lopez-GonzalezR, et al., 2021. p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR). Cell, 184(3):689-708.e20.

[44]MugurumaK, 2018. Self-organized cerebellar tissue from human pluripotent stem cells and disease modeling with patient-derived iPSCs. Cerebellum, 17(1):37-41.

[45]MugurumaK, NishiyamaA, KawakamiH, et al., 2015. Self-organization of polarized cerebellar tissue in 3D culture of human pluripotent stem cells. Cell Rep, 10(4):537-550.

[46]NanceMA, BerrySA, 1992. Cockayne syndrome: review of 140 cases. Am J Med Genet, 42(1):68-84.

[47]NewmanJC, BaileyAD, FanHY, et al., 2008. An abundant evolutionarily conserved CSB-PiggyBac fusion protein expressed in Cockayne syndrome. PLoS Genet, 4(3):e1000031.

[48]OkurMN, LeeJH, OsmaniW, et al., 2020. Cockayne syndrome group A and B proteins function in rRNA transcription through Nucleolin regulation. Nucleic Acids Res, 48(5):2473-2485.

[49]PaccosiE, Proietti-De-SantisL, 2021. The emerging role of Cockayne group A and B proteins in ubiquitin/proteasome-directed protein degradation. Mech Ageing Dev, 195:111466.

[50]PaccosiE, CostanzoF, CostantinoM, et al., 2020. The Cockayne syndrome group A and B proteins are part of a ubiquitin-proteasome degradation complex regulating cell division. Proc Natl Acad Sci USA, 117(48):30498-30508.

[51]ParkJ, WetzelI, MarriottI, et al., 2018. A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease. Nat Neurosci, 21(7):941-951.

[52]PiccioneM, Belloni FortinaA, FerriG, et al., 2021. Xeroderma pigmentosum: general aspects and management. J Pers Med, 11(11):1146.

[53]Proietti-De-SantisL, BalzeranoA, PranteraG, 2018. CSB: an emerging actionable target for cancer therapy. Trends Cancer, 4(3):172-175.

[54]QinYY, GuoT, LiGY, et al., 2015. CSB-PGBD3 mutations cause premature ovarian failure. PLoS Genet, 11(7):e1005419.

[55]RevetI, FeeneyL, TangAA, et al., 2012. Dysmyelination not demyelination causes neurological symptoms in preweaned mice in a murine model of Cockayne syndrome. Proc Natl Acad Sci USA, 109(12):4627-4632.

[56]SaccoR, TamblynL, RajakulendranN, et al., 2013. Cockayne syndrome b maintains neural precursor function. DNA Repair, 12(2):110-120.

[57]SarkarA, SimC, HongYS, et al., 2003. Molecular evolutionary analysis of the widespread piggyBac transposon family and related “domesticated” sequences. Mol Genet Genomics, 270(2):173-180.

[58]Scheibye-KnudsenM, RamamoorthyM, SykoraP, et al., 2012. Cockayne syndrome group B protein prevents the accumulation of damaged mitochondria by promoting mitochondrial autophagy. J Exp Med, 209(4):855-869.

[59]SelbyCP, SancarA, 1997. Cockayne syndrome group B protein enhances elongation by RNA polymerase II. Proc Natl Acad Sci USA, 94(21):11205-11209.

[60]SinY, TanakaK, SaijoM, 2016. The C-terminal region and SUMOylation of Cockayne syndrome group B protein play critical roles in transcription-coupled nucleotide excision repair. J Biol Chem, 291(3):1387-1397.

[61]SinY, MakimuraF, SaijoM, et al., 2018. Generation of splice switching oligonucleotides targeting the Cockayne syndrome group B gene product in order to change the diseased cell state. Biochem Biophys Res Commun, 500(2):163-169.

[62]SundbergM, TochitskyI, BuchholzDE, et al., 2018. Purkinje cells derived from TSC patients display hypoexcitability and synaptic deficits associated with reduced FMRP levels and reversed by rapamycin. Mol Psychiatry, 23(11):‍2167-2183.

[63]TakahashiDT, SatoY, YamagataA, et al., 2019. Structural basis of ubiquitin recognition by the winged-helix domain of Cockayne syndrome group B protein. Nucleic Acids Res, 47(7):3784-3794.

[64]TangXY, XuL, WangJS, et al., 2021. DSCAM/PAK1 pathway suppression reverses neurogenesis deficits in iPSC-derived cerebral organoids from patients with Down syndrome. J Clin Invest, 131(12):e135763.

[65]TiwariV, BaptisteBA, OkurMN, et al., 2021. Current and emerging roles of Cockayne syndrome group B (CSB) protein. Nucleic Acids Res, 49(5):2418-2434.

[66]van den HeuvelD, SpruijtCG, González-PrietoR, et al., 2021. A CSB-PAF1C axis restores processive transcription elongation after DNA damage repair. Nat Commun, 12:1342.

[67]van der HorstGTJ, van SteegH, BergRJW, et al., 1997. Defective transcription-coupled repair in Cockayne syndrome B mice is associated with skin cancer predisposition. Cell, 89(3):425-435.

[68]van der WeegenY, Golan-BermanH, MevissenTET, et al., 2020. The cooperative action of CSB, CSA, and UVSSA target TFIIH to DNA damage-stalled RNA polymerase II. Nat Commun, 11:2104.

[69]Vélez-CruzR, EglyJM, 2013. Cockayne syndrome group B (CSB) protein: at the crossroads of transcriptional networks. Mech Ageing Dev, 134(5-6):234-242.

[70]VessoniAT, HeraiRH, KarpiakJV, et al., 2016. Cockayne syndrome-derived neurons display reduced synapse density and altered neural network synchrony. Hum Mol Genet, 25(7):1271-1280.

[71]WangLF, LimboO, FeiJ, et al., 2014. Regulation of the Rhp26^ERCC6/CSB chromatin remodeler by a novel conserved leucine latch motif. Proc Natl Acad Sci USA, 111(52):18566-18571.

[72]WangS, MinZY, JiQZ, et al., 2020. Rescue of premature aging defects in Cockayne syndrome stem cells by CRISPR/Cas9-mediated gene correction. Protein Cell, 11(1):1-22.

[73]WangYM, ChakravartyP, RanesM, et al., 2014. Dysregulation of gene expression as a cause of Cockayne syndrome neurological disease. Proc Natl Acad Sci USA, 111(40):14454-14459.

[74]WangYM, Jones-TabahJ, ChakravartyP, et al., 2016. Pharmacological bypass of Cockayne syndrome B function in neuronal differentiation. Cell Rep, 14(11):2554-2561.

[75]Warre-CornishK, PerfectL, NagyR, et al., 2020. Interferon-‍γ signaling in human iPSC-derived neurons recapitulates neurodevelopmental disorder phenotypes. Sci Adv, 6(34):eaay9506.

[76]WeemsJC, SlaughterBD, UnruhJR, et al., 2021. A role for the Cockayne Syndrome B (CSB)‍-Elongin ubiquitin ligase complex in signal-dependent RNA polymerase II transcription. J Biol Chem, 297(1):100862.

[77]WeinerAM, GrayLT, 2013. What role (if any) does the highly conserved CSB-PGBD3 fusion protein play in Cockayne syndrome? Mech Ageing Dev, 134(5-6):225-233.

[78]WilsonBT, StarkZ, SuttonRE, et al., 2016. The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care. Genet Med, 18(5):483-493.

[79]XuYY, WuZZ, LiuLY, et al., 2019. Rat model of Cockayne syndrome neurological disease. Cell Rep, 29(4):800-809.e5.

[80]ZhaoXN, UsdinK, 2014. Gender and cell-type-specific effects of the transcription-coupled repair protein, ERCC6/CSB, on repeat expansion in a mouse model of the fragile X-related disorders. Hum Mutat, 35(3):341-349.