RESUMEN
DNA replication stress describes a state of impaired replication fork progress that triggers a cellular stress response to maintain genome stability and complete DNA synthesis. Replication stress is a common state that must be tolerated in many cancers. One promising therapeutic approach is targeting replication stress response factors such as the ataxia telangiectasia and rad 3-related kinase (ATR) or checkpoint kinase 1 (CHK1) kinases that some cancers depend upon to survive endogenous replication stress. However, research revealing the complexity of the replication stress response suggests new genetic interactions and candidate therapeutic targets. Many of these candidates regulate DNA transactions around reversed replication forks, including helicases, nucleases and alternative polymerases that promote fork stability and restart. Here we review emerging strategies to exploit replication stress for cancer therapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Reparación del ADN/efectos de los fármacos , Replicación del ADN/efectos de los fármacos , Proteínas de Unión al ADN/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Daño del ADN/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Inestabilidad Genómica , Humanos , Neoplasias/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Mutaciones Letales Sintéticas/efectos de los fármacosRESUMEN
Female-specific Ilp7 neuropeptide-expressing motoneurons (FS-Ilp7 motoneurons) are required in Drosophila for oviduct function in egg laying. Here, we uncover cellular and genetic mechanisms underlying their female-specific generation. We demonstrate that programmed cell death (PCD) eliminates FS-Ilp7 motoneurons in males, and that this requires male-specific splicing of the sex-determination gene fruitless (fru) into the FruMC isoform. However, in females, fru alleles that only generate FruM isoforms failed to kill FS-Ilp7 motoneurons. This blockade of FruM-dependent PCD was not attributable to doublesex gene function but to a non-canonical role for transformer (tra), a gene encoding the RNA splicing activator that regulates female-specific splicing of fru and dsx transcripts. In both sexes, we show that Tra prevents PCD even when the FruM isoform is expressed. In addition, we found that FruMC eliminated FS-Ilp7 motoneurons in both sexes, but only when Tra was absent. Thus, FruMC-dependent PCD eliminates female-specific neurons in males, and Tra plays a double-assurance function in females to establish and reinforce the decision to generate female-specific neurons.
