DNA Replication Stress and Chromosomal Instability: Dangerous Liaisons

Area of Science:

• Genetics and Molecular Biology
• Cell Biology
• Cancer Biology

Background:

• Chromosomal instability (CIN) is a hallmark of numerous diseases, including cancer, neurodevelopmental, and age-related disorders.
• Replication stress and mitotic errors are key drivers of structural (s-CIN) and numerical (n-CIN) chromosome instability, respectively.

Purpose of the Study:

• To review recent evidence on the mechanistic interconnections between replication stress and mitotic errors in driving CIN.
• To explore the downstream consequences of CIN, including inflammation, senescence, and chromothripsis.
• To discuss the dual role of CIN in non-cancerous versus cancerous cells and its therapeutic implications.

Main Methods:

• Review of current scientific literature on chromosomal instability.
• Analysis of mechanisms linking replication stress to structural and numerical CIN.
• Discussion of cellular outcomes and therapeutic strategies related to CIN.

Main Results:

• Replication stress can lead to both structural chromosome aberrations and numerical aneuploidy through mechanisms like mitotic rescue of replication stress (MRRS).
• Mitotic errors causing chromosome mis-segregation result in aneuploidy and micronucleation, which can trigger inflammation and senescence.
• CIN acts as an anticancer barrier in normal cells but promotes genomic instability in cancer, suggesting targeted therapeutic potential.

Conclusions:

• Structural and numerical CIN are mechanistically linked, with replication stress and mitotic errors playing interconnected roles.
• CIN has complex effects on cellular fitness and disease progression, acting as a barrier in some contexts and a driver in others.
• Targeting CIN pathways holds promise for novel cancer therapies by exploiting its dual role in cellular health and disease.