Exploring the genetic space of the DNA damage response for cancer therapy through CRISPR‐based screens

• Published in: Molecular oncology Vol. 16; no. 21; pp. 3778 - 3791
• Main Authors: Wilson, Jordan, Loizou, Joanna I.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.11.2022; John Wiley and Sons Inc; Wiley
• Subjects: Antimitotic agents; Antineoplastic agents; Apoptosis; Cancer; Cancer therapies; cancer therapy; Care and treatment; CRISPR; CRISPR-Cas Systems; CRISPR‐Cas9 screens; Deoxyribonucleic acid; DNA; DNA Damage; DNA damage response; DNA repair; drug discovery; Gene expression; Genes; Genetic aspects; Genetic screening; Genetic Testing; Genomes; Health aspects; Humans; Lethality; Microscopy; Mutation; Neoplasms - genetics; Phenotypes; Review; Reviews; synthetic lethality; synthetic viability; cancer therapy; CRISPR-Cas9 screens; drug discovery; DNA damage response; synthetic viability; synthetic lethality
• ISSN: 1574-7891; 1878-0261; 1878-0261
• DOI: 10.1002/1878-0261.13272

The concepts of synthetic lethality and viability have emerged as powerful approaches to identify vulnerabilities and resistances within the DNA damage response for the treatment of cancer. Historically, interactions between two genes have had a longstanding presence in genetics and have been identified through forward genetic screens that rely on the molecular basis of the characterized phenotypes, typically caused by mutations in single genes. While such complex genetic interactions between genes have been studied extensively in model organisms, they have only recently been prioritized as therapeutic strategies due to technological advancements in genetic screens. Here, we discuss synthetic lethal and viable interactions within the DNA damage response and present how CRISPR‐based genetic screens and chemical compounds have allowed for the systematic identification and targeting of such interactions for the treatment of cancer. The combination of CRISPR gene editing and drug treatments in a pooled screening format allows for the discovery of novel gene‐drug interactions. These interactions can potentially provide biomarkers for drug sensitivity and resistance in a clinical setting.