title: Loss of autophagy causes a synthetic lethal deficiency in DNA repair.
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.
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom; and.
authors.forename: Emma Y
authors.initials: EY
authors.lastname: Liu
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom; and Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Naihan
authors.initials: N
authors.lastname: Xu
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom; and.
authors.forename: Jim
authors.initials: J
authors.lastname: O'Prey
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom; and.
authors.forename: Laurence Y
authors.initials: LY
authors.lastname: Lao
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom; and.
authors.forename: Sanket
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom; and.
authors.forename: Jaclyn S
authors.initials: JS
authors.lastname: Long
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom; and.
authors.forename: Margaret
authors.initials: M
authors.lastname: O'Prey
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom; and.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Croft
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom; and.
authors.forename: Florian
authors.initials: F
authors.lastname: Beaumatin
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom; and.
authors.forename: Alice D
authors.initials: AD
authors.lastname: Baudot
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom; and.
authors.forename: Michaela
authors.initials: M
authors.lastname: Mrschtik
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom; and.
authors.forename: Mathias
authors.initials: M
authors.lastname: Rosenfeldt
authors.affiliation: Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Yaou
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom; and.
authors.forename: David A
authors.initials: DA
authors.lastname: Gillespie
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom; and k.ryan@beatson.gla.ac.uk.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Ryan
mesh_terms: D000818:Animals; D001343:Autophagy; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D004260:DNA Repair / Q000235:genetics*; D005804:Genes, Lethal; D059765:Homologous Recombination; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D017931:DNA Primers
keywords: DNA repair; autophagy; cell death; synthetic lethality