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

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 identi...

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Published inMolecular oncology Vol. 16; no. 21; pp. 3778 - 3791
Main Authors Wilson, Jordan, Loizou, Joanna I.
Format Journal Article
LanguageEnglish
Published United States John Wiley & Sons, Inc 01.11.2022
John Wiley and Sons Inc
Wiley
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Abstract 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.
AbstractList 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 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 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 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.
Audience Academic
Author Wilson, Jordan
Loizou, Joanna I.
AuthorAffiliation 1 Center for Cancer Research, Comprehensive Cancer Centre Medical University of Vienna Austria
2 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Vienna Austria
AuthorAffiliation_xml – name: 1 Center for Cancer Research, Comprehensive Cancer Centre Medical University of Vienna Austria
– name: 2 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Vienna Austria
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  givenname: Jordan
  orcidid: 0000-0001-7765-8597
  surname: Wilson
  fullname: Wilson, Jordan
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  givenname: Joanna I.
  orcidid: 0000-0003-1853-0424
  surname: Loizou
  fullname: Loizou, Joanna I.
  email: joanna.loizou@meduniwien.ac.at
  organization: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
BackLink https://www.ncbi.nlm.nih.gov/pubmed/35708734$$D View this record in MEDLINE/PubMed
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Issue 21
Keywords cancer therapy
CRISPR-Cas9 screens
drug discovery
DNA damage response
synthetic viability
synthetic lethality
Language English
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Snippet The concepts of synthetic lethality and viability have emerged as powerful approaches to identify vulnerabilities and resistances within the DNA damage...
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SubjectTerms 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
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Title Exploring the genetic space of the DNA damage response for cancer therapy through CRISPR‐based screens
URI https://onlinelibrary.wiley.com/doi/abs/10.1002%2F1878-0261.13272
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Volume 16
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