Stress-Induced Mutagenesis: Implications in Cancer and Drug Resistance

Abstract

Genomic instability underlies many cancers and generates genetic variation that drives cancer initiation, progression, and therapy resistance. In contrast with classical assumptions that mutations occur purely stochastically at constant, gradual rates, microbes, plants, flies, and human cancer cells possess mechanisms of mutagenesis that are upregulated by stress responses. These generate transient, genetic-diversity bursts that can propel evolution, specifically when cells are poorly adapted to their environments-that is, when stressed. We review molecular mechanisms of stress-response-dependent (stress-induced) mutagenesis that occur from bacteria to cancer, and are activated by starvation, drugs, hypoxia, and other stressors. We discuss mutagenic DNA break repair in Escherichia coli as a model for mechanisms in cancers. The temporal regulation of mutagenesis by stress responses and spatial restriction in genomes are common themes across the tree of life. Both can accelerate evolution, including the evolution of cancers. We discuss possible anti-evolvability drugs, aimed at targeting mutagenesis and other variation generators, that could be used to delay the evolution of cancer progression and therapy resistance.

Keywords: HSP90; MMBIR; chemotherapy; double-strand break repair; evolution; genome instability; hypoxia; kataegis; stress response; trinucleotide repeat instability.

Figure 1

Models of Escherichia coli MBR. (➀) DSBs arise via many routes. (a–c) RecBCD nuclease (an analog of human BRCA2) loads RecA HR protein (an ortholog of human RAD51) onto ssDNA, analogously to human BRCA2 loading RAD51, facilitating base-pairing with a strand of identical duplex DNA (blue) (e.g., a sister chromosome). Parallel lines represent base-paired DNA strands; arrowheads represent 3′ DNA ends. Repair synthesis (dashed lines) is switched to a mutagenic mode by the general stress response (sigma S; ➂). (d–f ) In HR-MBR, a switch to mutagenic HR repair of DSBs occurs when the SOS DNA damage response and general stress response are activated. (➁) The SOS response upregulates error-prone Pols IV, V, and II. (➂) The general stress response licenses the use of, or errors made by, alternative DNA polymerases in repair synthesis by as yet unknown means. DSB repair is otherwise high fidelity and dependent on high-fidelity DNA Pol III. HR-MBR produces (e) indels and (f) base substitutions, both dependent on Pol IV. Pol V contributes to some indels, and base substitutions. Pol II contributes to some indels. The red Xs represent DNA polymerase errors that become mutations. ( g,h) Microhomologous MBR requires DNA Pol I for template switching to regions containing microhomology ( g) and initiates replication, creating genome rearrangements (h) including duplications (blue arrows). Microhomologous MBR requires steps ➀ and ➂, but not the SOS response. Abbreviations: DSB, double-strand break; HR, homologous recombination; MBR, mutagenic break repair; Pol, DNA polymerase; SS, single-stranded.

Figure 2

Proposed anti-evolvability drugs for targeting the processes of cancer evolution. Current anticancer and antipathogen chemotherapies kill cells or inhibit growth and target the phenotypes of cancer—that is, the products of cancer evolution (right). Proposed anti-evolvability drugs would target the evolutionary processes that generate the variation that drives cancer (and pathogen) evolution, including the stress-response regulators that propel mutagenesis and the generators of nongenetic variation. Anti-evolvability drugs could slow evolution to allow other drugs and the immune system to work without inducing resistance. Multiple inputs into, and outputs from, one knot, referred to as bow ties, are universal organizational structures in biological and technological networks that confer evolvability and robustness and predict fragilities in disease (Csete & Doyle 2004).