An intact DNA-damage-response pathway is required to protect against tumorigenesis, and mutation of some genes that are known to be involved in the DNA-damage checkpoint, such as ATM and NBS1 , causes cancer-predisposition syndromes. MRE11 is also involved in this pathway, and is mutated in the ataxia-telangiectasia-like disorder (ATLD), but, until now, its role in cancer development has been unknown. In the March issue of EMBO Reports, Giuseppe Giannini et al. show that MRE11 is specifically mutated in mismatch-repair-deficient cancers, which impairs their response to DNA damage.

To determine whether MRE11 is mutated in human cancers, a 5′ fragment of the MRE11 transcript was amplified by polymerase chain reaction from a range of cell lines. Low levels of this fragment, and another product — a transcript that is deleted for exon 5 and encodes a truncated protein product — were obtained from several colorectal cancer cell lines, as well as a prostate cancer and an endometrial carcinoma cell line. These cell lines are all deficient in mismatch repair; so does this deficiency cause the MRE11 mutations?

Sequencing the mutated MRE11 gene revealed that the splice site 5′ to exon 5 contained deletions of one or two of the 11 thymine bases that are normally found — a mutation type that is frequently found in mismatch-repair-deficient cells. This reduces the efficiency of the splicing signal, which accounts for both the truncated product and the reduced expression of the wild-type product. Similar mutations were also found in mismatch-repair-deficient — but not mismatch-repair-proficient — primary colorectal cancers. The expression of both the mRNA and protein was also very low, indicating that the transcript might be degraded.

MRE11 forms a complex with NBS1 and RAD50 (the M–N–R complex), the integrity of which is required for the S-phase checkpoint and its relocalization to sites of DNA repair. So how is this process affected by mutations in MRE11? Expression of NBS1 and RAD50 is reduced in mismatch-repair-deficient cancer cells — a phenotype also observed in ATLD cells — and, following exposure to ionizing radiation, cells are resistant to both DNA synthesis inhibition and relocalization of the M–N–R complex to sites of repair. MRE11 is therefore an important target for mutation in mismatch-repair-deficient cancer cells.