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dc.contributor.authorWeeden, CE
dc.contributor.authorChen, Y
dc.contributor.authorMa, SB
dc.contributor.authorHu, Y
dc.contributor.authorRamm, G
dc.contributor.authorSutherland, KD
dc.contributor.authorSmyth, GK
dc.contributor.authorAsselin-Labat, M-L
dc.date.accessioned2020-12-22T04:13:37Z
dc.date.available2020-12-22T04:13:37Z
dc.date.issued2017-01-01
dc.identifierpii: pbio.2000731
dc.identifier.citationWeeden, C. E., Chen, Y., Ma, S. B., Hu, Y., Ramm, G., Sutherland, K. D., Smyth, G. K. & Asselin-Labat, M. -L. (2017). Lung Basal Stem Cells Rapidly Repair DNA Damage Using the Error-Prone Nonhomologous End-Joining Pathway. PLOS BIOLOGY, 15 (1), https://doi.org/10.1371/journal.pbio.2000731.
dc.identifier.issn1545-7885
dc.identifier.urihttp://hdl.handle.net/11343/258022
dc.description.abstractLung 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.
dc.languageEnglish
dc.publisherPUBLIC LIBRARY SCIENCE
dc.titleLung Basal Stem Cells Rapidly Repair DNA Damage Using the Error-Prone Nonhomologous End-Joining Pathway
dc.typeJournal Article
dc.identifier.doi10.1371/journal.pbio.2000731
melbourne.affiliation.departmentMedical Biology (W.E.H.I.)
melbourne.affiliation.departmentSchool of Mathematics and Statistics
melbourne.affiliation.department
melbourne.affiliation.departmentSurgery (St Vincent's)
melbourne.source.titlePLoS Biology
melbourne.source.volume15
melbourne.source.issue1
dc.rights.licenseCC BY
melbourne.elementsid1183634
melbourne.contributor.authorAsselin-Labat, Marie-Liesse
melbourne.contributor.authorSutherland, Kate
melbourne.contributor.authorSmyth, Gordon
melbourne.contributor.authorMA, STEPHEN
melbourne.contributor.authorWeeden, Claire
melbourne.contributor.authorChen, Yunshun
dc.identifier.eissn1545-7885
melbourne.accessrightsOpen Access


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