Causal link between microsatellite instability and hMRE11 dysfunction in human cancers

Abstract

Maintenance of genomic integrity is essential for cell survival, and genomic instability is a commonly recognized intrinsic property of all cancers. Microsatellite instability (MSI) represents a frequently occurring and easily traceable simple form of sequence variation, signified by the contraction or expansion of specific DNA sequences containing short tandem repeats. MSI is frequently detected in tumor cells with DNA mismatch repair (MMR) deficiency. It is commonly conceived that instability at individual microsatellite loci can arise spontaneously in cells independent of MMR status, and different microsatellite loci are generally not affected uniformly by MMR deficiency. It is well recognized that MMR deficiency per se is not sufficient to initiate tumorigenesis; rather, the biological effects have to be exerted by mutations in genes controlling cell survival, DNA damage response, and apoptosis. Recently, shortening of an intronic hMRE11 poly(T)11 tract has been associated with MMR deficiency, raising the possibility that hMRE11 may be inactivated by defective MMR. However, the molecular nature underlying this association is presently unknown, and review of the current literature suggests that hMRE11 is most likely involved with the MMR pathway in a more complex fashion than simply being a MMR target gene. An alternative scenario is proposed to better reconcile the differences among various studies. The potential role of hMRE11 in telomere repeats stability is also discussed.

Figure 1

Model for the effect of hMRE11 IVS-4 poly(T)11 mutation on MSI and MMR. In MSS colonic cells, 1 bp deletion at the hMRE11 poly(T)11 tract randomly arises from replication slippage, resulting in subtle reduction of full-length hMRE11 expression and a slight increase of the truncated hMRE11 protein. These in turn lead to MSI and MMR gene inactivation in clonal expanded cells, thereby promoting subsequent MMR target gene mutations and tumorigenesis. In MSI colonic cells, 1 bp deletion at the hMRE11 poly(T)11 tract is readily accumulated and exerts its biological effects in a similar fashion as stated above, whereas 2 bp deletion at the poly(T)11 tract has a more direct effect on tumorigenesis.