1. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China 2. FSU-CAS Innovation Institute, Foshan University, Foshan 528000, China 3. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China 4. Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA 5. Universidad Católica San Antonio de Murcia (UCAM) Campus de los Jerónimos, No 135 Guadalupe 30107, Murcia, Spain 6. Beijing Hospital of the Ministry of Health, Beijing 100730, China 7. Department of Gynecology and Obstetrics, Peking University Third Hospital, Beijing 100191, China 8. Department of Neurology, Peking University First Hospital, Beijing 100034, China 9. Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China 10. University of Chinese Academy of Sciences, Beijing 100049, China
Xeroderma pigmentosum (XP) is a group of genetic disorders caused by mutations of XP-associated genes, resulting in impairment of DNA repair. XP patients frequently exhibit neurological degeneration, but the underlying mechanism is unknown, in part due to lack of proper disease models. Here, we generated patientspecific induced pluripotent stem cells (iPSCs) harboring mutations in five different XP genes including XPA, XPB, XPC, XPG, and XPV. These iPSCs were further differentiated to neural cells, and their susceptibility to DNA damage stress was investigated. Mutation of XPA in either neural stem cells (NSCs) or neurons resulted in severe DNA damage repair defects, and these neural cells with mutant XPA were hyper-sensitive to DNA damage-induced apoptosis. Thus, XP-mutant neural cells represent valuable tools to clarify the molecular mechanisms of neurological abnormalities in the XP patients.
Andrade LND (2012) Evidence for premature aging due to oxidative stress in iPSCs from Cockayne syndrome . Hum Mol Genet 21(17):3825–3834
2
Andressoo JO (2009) An Xpb mouse model for combined Xeroderma pigmentosum and cockayne syndrome reveals progeroid features upon further attenuation of DNA repair . Mol Cell Biol 29(5):1276–1290
https://doi.org/10.1128/MCB.01229-08
Cattoglio C (2015) Functional and mechanistic studiesof XPC DNA-repair complex as transcriptional coactivator in embryonic stem cells . Proc Natl Acad Sci USA 112(18):E2317–E2326
5
Cheung HH (2014) Telomerase protects werner syndrome lineage-specific stem cells from premature aging . Stem Cell Reports 2(4):534–546
https://doi.org/10.1016/j.stemcr.2014.02.006
6
Chou KM (2011) DNA polymerase eta and chemotherapeutic agents . Antioxid Redox Signal 14(12):2521–2529
7
Cleaver JE (1968) Defective repair replication of DNA in xeroderma pigmentosum . Nature 218(5142):652–656
https://doi.org/10.1038/218652a0
8
Cleaver JE (1972) Xeroderma pigmentosum—variants with normal DNA-repair and normal sensitivity to ultraviolet-light . J Investig Dermatol 58(3):124–128
https://doi.org/10.1111/1523-1747.ep12538913
9
Cleaver JE, Lam ET, Revet I(2009) Disordersof nucleotide excision repair: the genetic and molecular basis of heterogeneity . Nat Rev Genet 10(11):756–768
https://doi.org/10.1038/nrg2663
10
De Weerd-Kastelein EA, Bootsma D, Keijzer W (1972) Genetic heterogeneity of Xeroderma pigmentosum demonstrated by somatic cell hybridization . Nature 238(81):80–83
https://doi.org/10.1038/newbio238080a0
11
Ding Z (2015) A widely adaptable approach to generate integration-free iPSCs from non-invasively acquired human somatic cells . Protein Cell 6(5):386–389
12
Duan S (2015) PTENdeficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype . Nat Commun 6:10068
https://doi.org/10.1038/ncomms10068
13
Epstein JH (1970) Defect in DNA synthesis in skin of patients with xeroderma pigmentosum demonstratedin vivo . Science 168 (3938):1477–1478
Grewal RP (1991) Neurons and DNA-Repair-Neurologic Involvement in Xeroderma Pigmentosa . Med Hypotheses 34(2):171–173
16
Hayashi M (2004) Brainstem and basal ganglia lesions in xeroderma pigmentosum group A . J Neuropathol Exp Neurol 63 (10):1048–1057
17
Khan SG (2004) Two essential splice lariat branchpoint sequences in one intron in a xeroderma pigmentosum DNA repair gene: mutations result in reduced XPC mRNA levels that correlate with cancer risk . Hum Mol Genet 13(3):343–352
18
Kulkarni A, Wilson DM (2008) The involvement of DNA-damage and-repair defects in neurological dysfunction . Am J Hum Genet 82 (3):539–566
19
Lai JP (2013) The influence of DNA repair on neurological degeneration, cachexia, skin cancer and internal neoplasms: autopsy report of four xeroderma pigmentosum patients (XP-A, XP-C and XP-D) . Acta Neuropathol Commun 1:4
https://doi.org/10.1186/2051-5960-1-4
20
Liu GH (2011a)Recapitulation of prematureageing with iPSCs from Hutchinson-Gilford progeria syndrome . Nature 472(7342):221–225
21
Liu GH (2011b) Targeted gene correction of laminopathyassociated LMNA mutations in patient-specific iPSCs . Cell Stem Cell 8(6):688–694
22
Liu GH (2012) Progressive degeneration of human neural stem cells caused by pathogenic LRRK2 . Nature 491(7425):603–607
23
Liu GH (2014) Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs . Nat Commun 5:4330
24
Maeda T (1994) Severe neurological abnormalities associated with a mutation in the zinc-finger domainina groupA Xeroderma pigmentosum patient . BrJ Dermatol 131(4):566–570
25
Masutani C(1999) The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta . Nature 399(6737): 700–704
26
Mocquet V (2008) Sequential recruitment of the repair factors during NER: the role of XPG in initiating the resynthesis step . EMBOJ 27(1):155–167
Nakagawa A (1998) Three-dimensional visualization of ultraviolet-induced DNA damage and its repair in human cell nuclei . Journal of Investigative Dermatology 110(2):143–148
29
Nakane H (1995) High incidence of ultraviolet-B-or chemical-carcinogen-induced skin tumoursin mice lacking the Xeroderma pigmentosum groupA gene . Nature 377(6545):165–168
30
Okita K(2011)A moreefficient method to generate integration-free human iPS cells . Nat Methods 8(5):409–412
31
Raya A (2009) Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells . Nature 460 (7251):U53–U61
32
Robbins JH (1974) Xeroderma pigmentosum: an inherited diseases with sun sensitivity, multiple cutaneous neoplasms, and abnormal DNA repair . Ann Intern Med 80(2):221–248
33
Scharer OD (2013) Nucleotide excision repair in eukaryotes . Cold Spring Harb Perspect Biol 5(10):a012609
34
Setlow RB, Setlow JK (1962) Evidence that ultraviolet-induced thymine dimers in DNA cause biological damage . Proc Natl Acad Sci USA 48(7):1250
35
Shimamoto A (2014) Reprogramming suppresses premature senescence phenotypes of Werner syndrome cells and maintains chromosomal stability over long-term culture . PLoS ONE 9(11): e112900
Xu XL (2014) Direct reprogramming of porcine fibroblasts to neural progenitor cells . Protein Cell 5(1):4–7
38
Yung SK (2013) Brief report: human pluripotent stem cell models of fanconi anemia deficiency reveal an important role for fanconi anemia proteins in cellular reprogramming and survival of hematopoietic progenitors . Stem Cells 31(5):1022–1029
39
Zhang WQ (2015)AWerner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging . Science 348(6239):1160–1168
