Loss of autophagy causes a synthetic lethal deficiency in DNA repair

Liu, E. Y. et al. (2015) Loss of autophagy causes a synthetic lethal deficiency in DNA repair. Proceedings of the National Academy of Sciences of the United States of America, 112(3), pp. 773-778. (doi:10.1073/pnas.1409563112)

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Abstract

(Macro)autophagy delivers cellular constituents to lysosomes for degradation. Although a cytoplasmic process, autophagy-deficient cells accumulate genomic damage, but an explanation for this effect is currently unclear. We report here that inhibition of autophagy causes elevated proteasomal activity leading to enhanced degradation of checkpoint kinase 1 (Chk1), a pivotal factor for the error-free DNA repair process, homologous recombination (HR). We show that loss of autophagy critically impairs HR and that autophagy-deficient cells accrue micronuclei and sub-G1 DNA, indicators of diminished genomic integrity. Moreover, due to impaired HR, autophagy-deficient cells are hyperdependent on nonhomologous end joining (NHEJ) for repair of DNA double-strand breaks. Consequently, inhibition of NHEJ following DNA damage in the absence of autophagy results in persistence of genomic lesions and rapid cell death. Because autophagy deficiency occurs in several diseases, these findings constitute an important link between autophagy and DNA repair and highlight a synthetic lethal strategy to kill autophagy-deficient cells.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Croft, Dr Daniel and Baudot, Dr Alice and Long, Dr Jaclyn and Ryan, Professor Kevin and Rosenfeldt, Dr Mathias and O'Prey, Mrs Margaret and Beaumatin, Dr Florian and Gillespie, Professor David and Joshi, Mr Sanket
Authors: Liu, E. Y., Xu, N., O’Prey, J., Lao, L. Y., Joshi, S., Long, J. S., O'Prey, M., Croft, D., Beaumatin, F., Baudot, A., Mrschtik, M., Rosenfeldt, M., Zhang, Y., Gillespie, D. A., and Ryan, K. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):0027-8424
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