title: A fine-scale dissection of the DNA double-strand break repair machinery and its implications for breast cancer therapy.
abstract: DNA-damage response machinery is crucial to maintain the genomic integrity of cells, by enabling effective repair of even highly lethal lesions such as DNA double-strand breaks (DSBs). Defects in specific genes acquired through mutations, copy-number alterations or epigenetic changes can alter the balance of these pathways, triggering cancerous potential in cells. Selective killing of cancer cells by sensitizing them to further DNA damage, especially by induction of DSBs, therefore requires careful modulation of DSB-repair pathways. Here, we review the latest knowledge on the two DSB-repair pathways, homologous recombination and non-homologous end joining in human, describing in detail the functions of their components and the key mechanisms contributing to the repair. Such an in-depth characterization of these pathways enables a more mechanistic understanding of how cells respond to therapies, and suggests molecules and processes that can be explored as potential therapeutic targets. One such avenue that has shown immense promise is via the exploitation of synthetic lethal relationships, for which the BRCA1-PARP1 relationship is particularly notable. Here, we describe how this relationship functions and the manner in which cancer cells acquire therapy resistance by restoring their DSB repair potential.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia QLD 4072, Australia.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia QLD 4072, Australia.
authors.forename: Sriganesh
authors.initials: S
authors.lastname: Srihari
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia QLD 4072, Australia Queensland Facility for Advanced Bioinformatics, The University of Queensland, St. Lucia 4072, Australia.
authors.forename: Kim-Anh Lê
authors.initials: KA
authors.lastname: Cao
authors.affiliation: QIMR-Berghofer Medical Research Institute, Herston, Brisbane, QLD 4029, Australia.
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
authors.affiliation: The University of Queensland Centre for Clinical Research, Herston, Brisbane, QLD 4029, Australia.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Simpson
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia QLD 4072, Australia kumkum.khanna@qimrberghofer.edu.au.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ragan
authors.affiliation: Queensland Facility for Advanced Bioinformatics, The University of Queensland, St. Lucia 4072, Australia kumkum.khanna@qimrberghofer.edu.au.
authors.forename: Kum Kum
authors.initials: KK
authors.lastname: Khanna
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D005260:Female; D006801:Humans; D059767:Recombinational DNA Repair