Efficient Pre-mRNA Cleavage Prevents Replication-Stress-Associated Genome Instability.

Area of Science:

• Molecular Biology
• Cancer Research
• Genomics

Background:

• Cellular mechanisms maintaining genome integrity are crucial and often dysregulated in cancer.
• Identifying genes that protect the genome in cancer is vital for therapeutic strategies.

Purpose of the Study:

• To identify novel cancer-related genome caretakers using a multi-screening approach.
• To investigate the role of pre-mRNA cleavage and polyadenylation complex in maintaining genome stability under replication stress.

Main Methods:

• Convergent multi-screening strategy combined with quantitative image-based cytometry.
• Ranking candidate genes based on viability, proliferation, replisome integrity, and DNA damage signaling.
• Assessing the impact of pre-mRNA cleavage deregulation on replication fork dynamics and DNA damage.

Main Results:

• Identified regulators of replication stress resilience, including components of the pre-mRNA cleavage and polyadenylation complex.
• Deregulation of pre-mRNA cleavage impairs replication fork speed and increases origin activity, leading to ATR dependency.
• Excessive RNA:DNA hybrid formation correlated with DNA damage; transcription inhibition rescued replication defects.
• Uncoupling pre-mRNA cleavage from co-transcriptional processing protected against replication-stress-associated DNA damage.

Conclusions:

• Pre-mRNA cleavage plays a critical role in managing replication stress and preventing genomic instability.
• Dysregulation of pre-mRNA cleavage contributes to DNA damage in cancer by promoting RNA:DNA hybrid formation and altering replication dynamics.
• Targeting pre-mRNA cleavage or its associated processes may offer novel therapeutic avenues for cancer treatment.