Microsatellite Instability and Aberrant Pre-mRNA Splicing: How Intimate Is It?

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Microsatellite instability (MSI) cancers constitute up to 15% of digestive tract malignancies.
• These cancers result from the inactivation of DNA Mismatch Repair (MMR) genes (e.g., MLH1, MSH2).
• MSI is linked to Lynch syndrome, an inherited cancer predisposition.

Purpose of the Study:

• To investigate the impact of MSI on DNA repair pathways and pre-mRNA splicing.
• To explore the functional link between MMR, DNA double-strand break (DSB) repair, and splicing machinery.

Main Methods:

• Analysis of gene mutations in MMR machinery.
• Identification of microsatellite (MS) shortening in 3'-intronic regions of ATM, MRE11, and HSP110.
• Assessment of aberrant pre-mRNA splicing and its effect on mature mRNA.

Main Results:

• Mutations in MMR genes lead to unrepaired DNA replication errors and thousands of mutations in repetitive sequences.
• Shortening of MS in 3'-intronic regions of ATM, MRE11, and HSP110 causes aberrant pre-mRNA splicing (exon skipping).
• Altered splicing of ATM and MRE11 impairs the MRE11/NBS1/RAD50 (MNR) DNA damage repair system.

Conclusions:

• MSI cancers exhibit a functional link between MMR and DSB repair systems and pre-mRNA splicing.
• Impaired splicing due to MS mutations in specific genes contributes to cancer progression.
• This highlights a novel mechanism by which MMR defects influence cellular repair pathways.