title: Lung Basal Stem Cells Rapidly Repair DNA Damage Using the Error-Prone Nonhomologous End-Joining Pathway.
abstract: Lung squamous cell carcinoma (SqCC), the second most common subtype of lung cancer, is strongly associated with tobacco smoking and exhibits genomic instability. The cellular origins and molecular processes that contribute to SqCC formation are largely unexplored. Here we show that human basal stem cells (BSCs) isolated from heavy smokers proliferate extensively, whereas their alveolar progenitor cell counterparts have limited colony-forming capacity. We demonstrate that this difference arises in part because of the ability of BSCs to repair their DNA more efficiently than alveolar cells following ionizing radiation or chemical-induced DNA damage. Analysis of mice harbouring a mutation in the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a key enzyme in DNA damage repair by nonhomologous end joining (NHEJ), indicated that BSCs preferentially repair their DNA by this error-prone process. Interestingly, polyploidy, a phenomenon associated with genetically unstable cells, was only observed in the human BSC subset. Expression signature analysis indicated that BSCs are the likely cells of origin of human SqCC and that high levels of NHEJ genes in SqCC are correlated with increasing genomic instability. Hence, our results favour a model in which heavy smoking promotes proliferation of BSCs, and their predilection for error-prone NHEJ could lead to the high mutagenic burden that culminates in SqCC. Targeting DNA repair processes may therefore have a role in the prevention and therapy of SqCC.
authors.affiliation: ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Clare E
authors.initials: CE
authors.lastname: Weeden
authors.affiliation: Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.|Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Yunshun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Ma
authors.affiliation: Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Yifang
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia.
authors.forename: Georg
authors.initials: G
authors.lastname: Ramm
authors.affiliation: ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Kate D
authors.initials: KD
authors.lastname: Sutherland
authors.affiliation: Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.affiliation: ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Marie-Liesse
authors.identifier: 0000-0001-7082-6076
authors.initials: ML
authors.lastname: Asselin-Labat
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016923:Cell Death; D002469:Cell Separation; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D059766:DNA End-Joining Repair; D004847:Epithelial Cells / Q000166:cytology / Q000648:ultrastructure; D006801:Humans; D008168:Lung / Q000166:cytology*; D008175:Lung Neoplasms / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D018307:Neoplasms, Squamous Cell / Q000473:pathology; D011650:Pulmonary Alveoli / Q000166:cytology; D012907:Smoking / Q000009:adverse effects; D013234:Stem Cells / Q000166:cytology*; D014132:Trachea / Q000166:cytology
chemical_list: D015415:Biomarkers