Replication stress links structural and numerical cancer chromosomal instability

Area of Science:

• Genetics
• Molecular Biology
• Cancer Research

Background:

• Cancer chromosomal instability (CIN) is linked to poor prognosis and drug resistance in solid tumors.
• Understanding the mechanisms driving CIN is crucial for developing effective cancer therapies.
• CIN generates intratumour heterogeneity, complicating treatment strategies.

Purpose of the Study:

• To investigate the mechanistic basis of chromosomal instability (CIN) in colorectal cancer (CRC).
• To identify novel genes and pathways involved in the development and maintenance of CIN.
• To explore potential therapeutic targets for mitigating CIN-driven heterogeneity.

Main Methods:

• Comparative analysis of DNA replication stress and fork progression in CIN(+) and CIN(-) CRC cells.
• Identification and characterization of CIN-suppressor genes on chromosome 18q.
• Assessment of the impact of gene silencing and nucleoside supplementation on chromosome segregation and DNA damage.

Main Results:

• Impaired replication fork progression and increased DNA replication stress observed in CIN(+) CRC cells.
• Three novel CIN-suppressor genes (PIGN, MEX3C, ZNF516) on chromosome 18q identified, frequently lost in CIN(+) CRC.
• Loss of these genes leads to replication stress, structural chromosome abnormalities, and missegregation.
• Nucleoside supplementation reduced segregation errors and DNA damage in CIN(+) cells and after gene silencing.

Conclusions:

• Replication stress plays a central role in generating both structural and numerical CIN.
• Chromosome 18q loss and subsequent silencing of CIN-suppressor genes contribute to aneuploidy onset.
• Targeting replication stress presents a promising therapeutic avenue to limit intratumour heterogeneity in CRC.