DOI: 10.1073/pnas.96.26.15038. Human cells compromised for p53 function exhibit defective global and transcription-coupled nucleotide excision repair, whereas cells compromised for pRb function are defective only in global repair

Human cells compromised for p53 function exhibit defective global and transcription-coupled nucleotide excision repair, whereas cells compromised for pRb function are defective only in global repair

10.1073/pnas.96.26.15038

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

After exposure to DNA-damaging agents, the p53 tumor suppressor protects against neoplastic transformation by inducing growth arrest and apoptosis. A series of investigations has also demonstrated that, in UV-exposed cells, p53 regulates the removal of DNA photoproducts from the genome overall (global nucleotide excision repair), but does not participate in an overlapping pathway that removes damage specifically from the transcribed strand of active genes (transcription-coupled nucleotide excision repair). Here, the highly sensitive ligation-mediated PCR was employed to quantify, at nucleotide resolution, the repair of UVB-induced cyclobutane pyrimidine dimers (CPDs) in genetically p53-deficient Li–Fraumeni skin fibroblasts, as well as in human lung fibroblasts expressing the human papillomavirus (HPV) E6 oncoprotein that functionally inactivates p53. Lung fibroblasts expressing the HPV E7 gene product, which similarly inactivates the retinoblastoma tumor-suppressor protein (pRb), were also investigated. pRb acts downstream of p53 to mediate G 1 arrest, but has no demonstrated role in DNA repair. Relative to normal cells, HPV E6-expressing lung fibroblasts and Li–Fraumeni skin fibroblasts each manifested defective CPD repair along both the transcribed and nontranscribed strands of the p53 and/or c- jun loci. HPV E7-expressing lung fibroblasts also exhibited reduced CPD removal, but only along the nontranscribed strand. Our results provide striking evidence that transcription-coupled repair, in addition to global repair, are p53-dependent in UV-exposed human fibroblasts. Moreover, the observed DNA-repair defect in HPV E7-expressing cells reveals a function for this oncoprotein in HPV-mediated carcinogenesis, and may suggest a role for pRb in global nucleotide excision repair.

Bibliography

Therrien, J.-P., Drouin, R., Baril, C., & Drobetsky, E. A. (1999). Human cells compromised for p53 function exhibit defective global and transcription-coupled nucleotide excision repair, whereas cells compromised for pRb function are defective only in global repair. Proceedings of the National Academy of Sciences, 96(26), 15038â15043.

Authors 4

Jean-Philippe Therrien (first)
Régen Drouin (additional)
Caroline Baril (additional)
Elliot A. Drobetsky (additional)

References 61 Referenced 65

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Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:35 a.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 5:17 p.m.)
Indexed	1 year, 1 month ago (July 30, 2024, 3:54 p.m.)
Issued	25 years, 8 months ago (Dec. 21, 1999)
Published	25 years, 8 months ago (Dec. 21, 1999)
Published Online	25 years, 8 months ago (Dec. 21, 1999)
Published Print	25 years, 8 months ago (Dec. 21, 1999)

Funders 0

None

BibTeX

@article{Therrien_1999, title={Human cells compromised for p53 function exhibit defective global and transcription-coupled nucleotide excision repair, whereas cells compromised for pRb function are defective only in global repair}, volume={96}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.96.26.15038}, DOI={10.1073/pnas.96.26.15038}, number={26}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Therrien, Jean-Philippe and Drouin, Régen and Baril, Caroline and Drobetsky, Elliot A.}, year={1999}, month=dec, pages={15038–15043} }

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