תובנה - Genomics - # DNA Damage Tolerance

Molecular Dependencies and Genomic Consequences of a Global DNA Damage Tolerance Defect

Q: How does the CST complex contribute to fork stability in DDT-deficient cells

In DDT-deficient cells, the CST complex plays a crucial role in maintaining fork stability. The CST complex consists of CDC13/CTC1, STN1, and TEN1, which are involved in various DNA repair processes. Specifically, CST promotes fork stability by blocking MRE11-mediated degradation of nascent DNA strands and protecting stalled replication forks. This function helps prevent excessive fork stalling and collapse that can occur in the absence of functional DDT pathways like translesion synthesis (TLS) or template switching (TS). By stabilizing the replisome and facilitating proper DNA replication under challenging conditions such as replication stress or genotoxic insults, the CST complex ensures genome integrity and cell survival.

Q: What implications do type 3 deletions have for cancer development and treatment

Type 3 deletions have significant implications for cancer development and treatment. These large genomic deletions ranging from 0.4 to 4.0 kbp are associated with replication stress-induced mutagenesis observed in DDT-deficient cells. In human tumors, type 3 deletions are prevalent across different tumor types and can dominate the deletion landscape. The presence of these specific deletions is linked to defects in DNA repair genes and correlates with increased sensitivity to certain treatments like chemotherapy or immunotherapy. From a cancer perspective, type 3 deletions serve as a mutational signature of replication stress that can drive tumorigenesis by promoting genomic instability through large-scale structural variations. Understanding the molecular mechanisms underlying type 3 deletions could provide insights into novel therapeutic targets for cancer treatment strategies aimed at exploiting vulnerabilities associated with this specific mutational signature.

Q: How can the findings from mouse models be translated into potential therapeutic strategies for human cancers

The findings from mouse models regarding DDT deficiency offer valuable insights that can be translated into potential therapeutic strategies for human cancers: Targeting Replication Stress: Understanding how DDT deficiency leads to increased replication stress and genomic instability can guide the development of therapies targeting key components involved in maintaining genome integrity during DNA replication. Exploiting Vulnerabilities: Identifying vulnerabilities associated with specific types of mutations like type 3 deletions could inform targeted therapies aimed at exploiting these vulnerabilities unique to cancer cells while sparing normal cells. Personalized Treatment Approaches: Utilizing knowledge about genetic dependencies identified through mouse models allows for personalized treatment approaches based on individual tumor characteristics such as mutation profiles related to DDT deficiencies. 4 .Drug Development: Insights gained from studying molecular dependencies in response to global DDT defects may lead to the development of new drugs targeting critical pathways involved in maintaining genome stability under replicative stress conditions seen in cancers. By leveraging these translational opportunities derived from preclinical studies using mouse models deficient in key DNA damage tolerance pathways like PCNA-Ub and REV1, researchers can potentially advance precision medicine approaches tailored towards improving outcomes for patients with diverse forms of cancer characterized by similar genomic instabilities seen in experimental settings involving disrupted DDR networks due to compromised DDT systems."

מושגי ליבה

The DDT system plays a crucial role in genome maintenance, preventing large deletions and promoting replication stability.

תקציר

The study focused on PcnaK164R/-;Rev1-/- compound mutants to analyze the impact of a global DNA damage tolerance defect. DM cells showed increased replication stress, hypersensitivity to genotoxic agents, and altered replication speed. A CRISPR-Cas9 screen identified CST complex reliance in DM cells for fork stability. Whole-genome sequencing revealed type 3 deletions as a mutational signature of replication stress. Human tumors also exhibited type 3 deletions associated with DNA damage response status and treatment modality.

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biorxiv.org

סטטיסטיקה

Double mutant (DM) cells displayed increased replication stress.
Whole genome CRISPR-Cas9 screen revealed reliance on the CST complex.
Type 3 deletions favored by DM DDT defect were 0.4-4.0kbp.
Human tumors showed an abundance of type 3 deletions.

ציטוטים

"Our data highlight the essential contribution of the DDT system to genome maintenance."
"Type 3 deletions are abundant in human tumors and are associated with DNA damage response status."

תובנות מפתח מזוקקות מ:

Molecular dependencies and genomic consequences of a global DNA damage tolerance defect

by de Groot,D.,... ב- www.biorxiv.org 10-11-2023

https://www.biorxiv.org/content/10.1101/2023.10.11.561854v2

שאלות מעמיקות

How does the CST complex contribute to fork stability in DDT-deficient cells

In DDT-deficient cells, the CST complex plays a crucial role in maintaining fork stability. The CST complex consists of CDC13/CTC1, STN1, and TEN1, which are involved in various DNA repair processes. Specifically, CST promotes fork stability by blocking MRE11-mediated degradation of nascent DNA strands and protecting stalled replication forks. This function helps prevent excessive fork stalling and collapse that can occur in the absence of functional DDT pathways like translesion synthesis (TLS) or template switching (TS). By stabilizing the replisome and facilitating proper DNA replication under challenging conditions such as replication stress or genotoxic insults, the CST complex ensures genome integrity and cell survival.

What implications do type 3 deletions have for cancer development and treatment

Type 3 deletions have significant implications for cancer development and treatment. These large genomic deletions ranging from 0.4 to 4.0 kbp are associated with replication stress-induced mutagenesis observed in DDT-deficient cells. In human tumors, type 3 deletions are prevalent across different tumor types and can dominate the deletion landscape. The presence of these specific deletions is linked to defects in DNA repair genes and correlates with increased sensitivity to certain treatments like chemotherapy or immunotherapy.
From a cancer perspective, type 3 deletions serve as a mutational signature of replication stress that can drive tumorigenesis by promoting genomic instability through large-scale structural variations. Understanding the molecular mechanisms underlying type 3 deletions could provide insights into novel therapeutic targets for cancer treatment strategies aimed at exploiting vulnerabilities associated with this specific mutational signature.

How can the findings from mouse models be translated into potential therapeutic strategies for human cancers

The findings from mouse models regarding DDT deficiency offer valuable insights that can be translated into potential therapeutic strategies for human cancers:

Targeting Replication Stress: Understanding how DDT deficiency leads to increased replication stress and genomic instability can guide the development of therapies targeting key components involved in maintaining genome integrity during DNA replication.

Exploiting Vulnerabilities: Identifying vulnerabilities associated with specific types of mutations like type 3 deletions could inform targeted therapies aimed at exploiting these vulnerabilities unique to cancer cells while sparing normal cells.

Personalized Treatment Approaches: Utilizing knowledge about genetic dependencies identified through mouse models allows for personalized treatment approaches based on individual tumor characteristics such as mutation profiles related to DDT deficiencies.

4 .Drug Development: Insights gained from studying molecular dependencies in response to global DDT defects may lead to the development of new drugs targeting critical pathways involved in maintaining genome stability under replicative stress conditions seen in cancers.
By leveraging these translational opportunities derived from preclinical studies using mouse models deficient in key DNA damage tolerance pathways like PCNA-Ub and REV1, researchers can potentially advance precision medicine approaches tailored towards improving outcomes for patients with diverse forms of cancer characterized by similar genomic instabilities seen in experimental settings involving disrupted DDR networks due to compromised DDT systems."