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. 2023 Jan 25;14(2):311.
doi: 10.3390/genes14020311.

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

Laurent Corcos  1   2 , Enora Le Scanf  1 , Gaël Quéré  1 , Danielle Arzur  1 , Gwennina Cueff  1 , Catherine Le Jossic-Corcos  1 , Cédric Le Maréchal  1   2
Affiliations

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

Laurent Corcos et al. Genes (Basel). .

Abstract

Cancers that belong to the microsatellite instability (MSI) class can account for up to 15% of all cancers of the digestive tract. These cancers are characterized by inactivation, through the mutation or epigenetic silencing of one or several genes from the DNA MisMatch Repair (MMR) machinery, including MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, PMS2 and Exo1. The unrepaired DNA replication errors turn into mutations at several thousand sites that contain repetitive sequences, mainly mono- or dinucleotides, and some of them are related to Lynch syndrome, a predisposition condition linked to a germline mutation in one of these genes. In addition, some mutations shortening the microsatellite (MS) stretch could occur in the 3'-intronic regions, i.e., in the ATM (ATM serine/threonine kinase), MRE11 (MRE11 homolog) or the HSP110 (Heat shock protein family H) genes. In these three cases, aberrant pre-mRNA splicing was observed, and it was characterized by the occurrence of selective exon skipping in mature mRNAs. Because both the ATM and MRE11 genes, which as act as players in the MNR (MRE11/NBS1 (Nibrin)/RAD50 (RAD50 double strand break repair protein) DNA damage repair system, participate in double strand breaks (DSB) repair, their frequent splicing alterations in MSI cancers lead to impaired activity. This reveals the existence of a functional link between the MMR/DSB repair systems and the pre-mRNA splicing machinery, the diverted function of which is the consequence of mutations in the MS sequences.

Keywords: DNA damage; DNA replication errors; digestive cancers; microsatellite instability; pre-mRNA splicing.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Generic splice unit. ESE: Exonic Splice Enhancer, ESS: Exonic Splice Silencer, ISE: Intronic Splice Enhancer, ISS: Intronic Splice Silencer, PPT: polypyrimidine tract, hnRNP: heterogenous nuclear ribonucleic particle, snRNP: small nuclear ribonucleic particle, SR: serine arginine-rich RNA-binding protein.
Figure 2
Figure 2
MSS and MSI splicing in cases of DNA replication errors. WT: Wild Type; MUT: Mutant. DNA replication errors may be fixed (MSS cancer) or not fixed (MSI cancer).
Figure 3
Figure 3
Model of incidence of pre-mRNA splicing errors in MSI cancer progression. DNA damage and replication errors trigger exon skipping in genes with intronic PPT shortening. The corresponding pre-mRNA structures are changed such that the function of the gene may be changed or the mRNA be targeted to the NMD surveillance system and degraded. The same errors may then be produced over again over the course of the cancer progression.
See this image and copyright information in PMC

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