Cancer therapy and replication stress: forks on the road to perdition.
Deregulated DNA replication occurs in cancer where it contributes to genomic instability. This process is a target of cytotoxic therapies. Chemotherapies exploit high DNA replication in cancer cells by modifying the DNA template or by inhibiting vital enzymatic activities that lead to slowing or stalling replication fork progression. Stalled replication forks can be converted into toxic DNA double-strand breaks resulting in cell death, i.e., replication stress. While likely crucial for many cancer treatments, replication stress is poorly understood due to its complexity. While we still know relatively little about the role of replication stress in cancer therapy, technical advances in recent years have shed new light on the effect that cancer therapeutics have on replication forks and the molecular mechanisms that lead from obstructed fork progression to cell death. This chapter will give an overview of our current understanding of replication stress in the context of cancer therapy.
School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
Panagiotis
P
Kotsantis
School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
Rebecca M
RM
Jones
School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
Martin R
MR
Higgs
School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom. Electronic address: e.petermann@bham.ac.uk.
Eva
E
Petermann
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D016923:Cell Death; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication / Q000187:drug effects; D059765:Homologous Recombination; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology
D000970:Antineoplastic Agents; D019384:Nucleic Acid Synthesis Inhibitors
Cell cycle; Checkpoint; DNA damage; DNA repair; DNA replication; Homologous recombination; Replication fork; Replication stress; S phase