title: The Nucleotide Excision Repair Pathway Limits L1 Retrotransposition.
abstract: Long interspersed elements 1 (L1) are active mobile elements that constitute almost 17% of the human genome. They amplify through a "copy-and-paste" mechanism termed retrotransposition, and de novo insertions related to these elements have been reported to cause 0.2% of genetic diseases. Our previous data demonstrated that the endonuclease complex ERCC1-XPF, which cleaves a 3' DNA flap structure, limits L1 retrotransposition. Although the ERCC1-XPF endonuclease participates in several different DNA repair pathways, such as single-strand annealing, or in telomere maintenance, its recruitment to DNA lesions is best characterized in the nucleotide excision repair (NER) pathway. To determine if the NER pathway prevents the insertion of retroelements in the genome, we monitored the retrotransposition efficiencies of engineered L1 elements in NER-deficient cells and in their complemented versions. Core proteins of the NER pathway, XPD and XPA, and the lesion binding protein, XPC, are involved in limiting L1 retrotransposition. In addition, sequence analysis of recovered de novo L1 inserts and their genomic locations in NER-deficient cells demonstrated the presence of abnormally large duplications at the site of insertion, suggesting that NER proteins may also play a role in the normal L1 insertion process. Here, we propose new functions for the NER pathway in the maintenance of genome integrity: limitation of insertional mutations caused by retrotransposons and the prevention of potentially mutagenic large genomic duplications at the site of retrotransposon insertion events.
authors.affiliation: Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane Cancer Center, Tulane University, New Orleans, Louisiana 70112.|Department of Structural and Cellular Biology, School of Medicine, Tulane Cancer Center, Tulane University, New Orleans, Louisiana 70112.
authors.forename: Geraldine
authors.identifier: 0000-0002-6124-8558
authors.initials: G
authors.lastname: Servant
authors.affiliation: Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane Cancer Center, Tulane University, New Orleans, Louisiana 70112.|Department of Structural and Cellular Biology, School of Medicine, Tulane Cancer Center, Tulane University, New Orleans, Louisiana 70112.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Streva
authors.affiliation: Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane Cancer Center, Tulane University, New Orleans, Louisiana 70112.|Department of Structural and Cellular Biology, School of Medicine, Tulane Cancer Center, Tulane University, New Orleans, Louisiana 70112.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Derbes
authors.affiliation: Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane Cancer Center, Tulane University, New Orleans, Louisiana 70112.|Department of Structural and Cellular Biology, School of Medicine, Tulane Cancer Center, Tulane University, New Orleans, Louisiana 70112.
authors.forename: Madushani I
authors.initials: MI
authors.lastname: Wijetunge
authors.affiliation: Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane Cancer Center, Tulane University, New Orleans, Louisiana 70112.|Department of Structural and Cellular Biology, School of Medicine, Tulane Cancer Center, Tulane University, New Orleans, Louisiana 70112.
authors.forename: Marc
authors.initials: M
authors.lastname: Neeland
authors.affiliation: Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane Cancer Center, Tulane University, New Orleans, Louisiana 70112.|Department of Structural and Cellular Biology, School of Medicine, Tulane Cancer Center, Tulane University, New Orleans, Louisiana 70112.
authors.forename: Travis B
authors.initials: TB
authors.lastname: White
authors.affiliation: Department of Structural and Cellular Biology, School of Medicine, Tulane Cancer Center, Tulane University, New Orleans, Louisiana 70112.|Tulane Center for Aging, Tulane University, New Orleans, Louisiana 70112.
authors.forename: Victoria P
authors.initials: VP
authors.lastname: Belancio
authors.affiliation: Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane Cancer Center, Tulane University, New Orleans, Louisiana 70112.|Department of Structural and Cellular Biology, School of Medicine, Tulane Cancer Center, Tulane University, New Orleans, Louisiana 70112.
authors.forename: Astrid M
authors.identifier: 0000-0002-8884-4544
authors.initials: AM
authors.lastname: Roy-Engel
authors.affiliation: Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane Cancer Center, Tulane University, New Orleans, Louisiana 70112 pdeinin@tulane.edu.|Department of Structural and Cellular Biology, School of Medicine, Tulane Cancer Center, Tulane University, New Orleans, Louisiana 70112.
authors.forename: Prescott L
authors.identifier: 0000-0002-1067-3028
authors.initials: PL
authors.lastname: Deininger
mesh_terms: D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D015894:Genome, Human; D023281:Genomics; D006367:HeLa Cells; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics / Q000378:metabolism; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; C095888:xeroderma pigmentosum group F protein; C071447:ERCC1 protein, human; D004720:Endonucleases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human
keywords: DNA damage; L1 retrotransposon; genome stability; nucleotide excision repair; target-primed reverse transcription