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The MRE11/RAD50/NBS1 Complex Destabilization in Lynch-Syndrome Patients

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The MRE11/RAD50/NBS1 Complex Destabilization in Lynch-Syndrome Patients European Journal of Human Genetics (2007) 15, 922–929 & 2007 Nature Publishing Group All rights reserved 1018-4813/07 $30.00 www.nature.com/ejhg ARTICLE The MRE11/RAD50/NBS1 complex destabilization in Lynch-syndrome patients Aster Alemayehu1 and Ivana Fridrichova*,1 1Laboratory of Cancer Genetics, Cancer Research Institute of Slovak Academy of Sciences, Bratislava, Slovakia Lynch syndrome is an inherited disease leading to the development predominantly of colorectal cancer (CRC). The crucial cause is malfunction of DNA mismatch repair that is characterized by high level of microsatellite instability; however, new knowledge of two MSI modes (types A and B) suggests a more complex molecular basis of this syndrome. To investigate, whether the extensive alterations in individual MSI markers (type B) can indicate the potential deficiency of DNA double-strand break (DSB) repair in Lynch-syndrome-related tumours, we evaluated the MSI type and alterations in the MRE11 and RAD50 repeats that are associated with the reduced protein expression and functional impairment of the MRE11– RAD50–NBS1 (MRN) complex. Of 27 CRCs, 21 samples manifested type B in at least one MSI þ marker. From type B tumours, the genetic alterations were identified in 16 (76%) samples; seven, one and eight cases manifested mutations in MRE11, RAD50 and both genes, respectively. However, predominantly biallelic MRE11 alterations with simultaneously developed RAD50 mutations impaired the protein expressions with different intensity and location in tumour. Of six tumours presenting changes p6bp (type A), in four samples identical alterations and protein expressions were observed. Moreover, in two patients with different MSI types germline insertions in the MRE11(T)11 were found. Overall, our findings indicate the absence of significant association between type B MSI and MRE11 or RAD50 mutations in tumours of Lynch-syndrome patients, but a subset of them manifested causal mutations for MRN destabilization that could lead to the additional defect in DSB repair. European Journal of Human Genetics (2007) 15, 922–929; doi:10.1038/sj.ejhg.5201858; published online 30 May 2007 Keywords: Lynch syndrome; microsatellite instability; two types of MSI; MRE11; RAD50 Introduction is the high level of instability in repetitive sequences, Lynch syndrome (hereditary non-polyposis colorectal microsatellites (MSI-H). cancer – HNPCC) is an autosomal-dominant disease that The introduction of a new fluorescent technique enables results in several types of cancer, predominantly those the recognition of the two types of instability in dinucleo- located in the colon, rectum or endometrium. It is tide microsatellites of different origin. MSI marker of type generally accepted that tumour development is initiated A was characterized by short insertions and deletions of up by DNA mismatch repair (MMR) malfunction that is to 6 bp, as a direct consequence of MMR deficiency. Type B caused by germline mutations in MMR genes, mostly in is represented by more extensive changes of X8 bp that are MLH1 and MSH2. The significant hallmark of MMR defects caused by an additional molecular mechanism other than MMR inactivation, probably by inappropriate recombina- *Correspondence: Dr I Fridrichova, Laboratory of Cancer Genetics, Cancer tional DNA repair. The former type was frequently Research Institute of Slovak Academy of Sciences, Vlarska 7, 833 91 observed in mice, human cell lines and patients suffered Bratislava, Slovakia. Tel: þ 421 2 59327 208; Fax: þ 421 2 59327 250; from rectal tumours with low levels of MSI (MSI-L),1,2 the E-mail: [email protected] Received 21 September 2006; revised 4 April 2007; accepted 24 April latter in various malignancies, including Lynch-syndrome 3 2007; published online 30 May 2007 cancers. The MRN destabilization in Lynch syndrome A Alemayehu and I Fridrichova 923 Maintenance of genomic integrity during the DNA molecular basis of MLH1 mutations in a subset of Lynch- replication process is provided by a group of BRCA1- syndrome patients.16 associated proteins of the BASC supercomplex that is Previously characterized MSI in cancers of Lynch- considered to be a sensor for DNA damage.4 The compo- syndrome patients manifested mainly type B MSI, as type nents of this complex are MMR proteins and also a A MSI was not recognized by formerly utilized isotopic- heterotrimer MRE11–RAD50–NBS1 (MRN) which is essen- labelled PCR assay.17 However, more extensive alterations tial for DNA double-strand break (DSB) repair performing of dinucleotide repeats described in MSI þ cancer cell lines by homologous recombination (HR) or non-homologous and unselected gastrointestinal tumours could reflect the end joining (NHEJ).5 Recent evidence indicates that multi- deficiency of recombinational DNA repair. To investigate, ple activities of several proteins occur in different path- whether or not type B MSI can indicate the potential ways, such as the role of MSH2 protein in signalling and deficiency of DSB repair in tumours related to Lynch cell-cycle regulation of ATM and MRN complex6 or direct syndrome, we evaluated the MSI type and alterations in association of MRE11 and MLH1 proteins, which can result repetitive sequences of the MRE11 and RAD50 genes with in mutual cooperation during DNA-damage detection, corresponding protein expressions in hereditary CRCs. signalling and repair.7 Relation between the malfunction of MMR and aberrant recombinational DNA repair in animal and human cancer cells has previously been observed. Mouse MSH2-deficient Patients and methods cells have lost the dependence of complete identity In total, the samples from 33 patients were collected for between interacting DNA sequences in the process of HR our study; of these, 27 MSI-H tumours developed in 25 repair.8 Similarly, in mouse embryonic stem cells and Lynch-syndrome patients and single CRCs in eight patients human tumour cell lines that have the MSH2 mutation, the with MSI-L phenotype in an average age of 38.378.7 and barrier to recombination between diverged substrates was 38.4711 years, respectively. All persons fulfilled Amster- relaxed and DSBs were repaired predominantly by non- dam criteria or Bethesda Guidelines. In most of the patients reciprocal HR – gene conversion.9,10 with MSI-H phenotype, the MMR germline mutations were Mismatch-repair-deficient tumours are characterized by detected by genomic sequencing.18,19 The identification of widespread changes in the number of microsatellites inherited genetic alterations in the rest of patients by accumulating in both coding and non-coding sequences sequencing or MLPA analysis for recognition of long of many human genes. Genetic alterations occurring in deletions is still in process. coding repeats result in frameshift mutations and the The evaluation of MSI type was performed on matched expression of inactive proteins. The changes in intronic DNA samples (normal/tumour). The samples were analysed microsatellites can also lead to functional changes, if they by a high-resolution fluorescent-labelling method using are located in regulatory regions of genes. In a series of 5–9 highly polymorphic dinucleotide markers: D2S378, unstable gastric and colorectal cancers (CRCs), mono- or D2S123, D2S391, D3S1561, D3S1611, D3S3685, D5S346, 20 biallelic deletions in the poly(T)11 within MRE11 intron 4 D17S250 and D18S34, as described previously. Forward were detected that cause aberrant splicing signals, skipping primer for each MSI marker was labelled on the 50-end by of exon 5, introduction of a premature stop codon and fluorescent dye (FAM, HEX or NED). The PCR products generation of a truncated protein. However, only larger were analysed using ABI PRISM 310 Genetic Analyzer and biallelic shortening corresponds with the strong (Applied Biosystems, Foster City, CA, USA) and collected reduction or absence of MRE11 protein expression.11,12 data were evaluated by GeneScan software. Tumours were Additionally, the results of two independent studies have classified as MSI-H if at least 30% of markers manifested an documented the high frequency of frameshift mutations in instability, and as MSI-L if less than 30% positive MSI the (A)9 repeat that is located in RAD50 exon 13, but no markers were identified. The MSI þ markers were char- mutations were found in the (A)7 tract of the NBS1 gene in acterized by length of alteration: type A manifested primary gastrointestinal carcinomas with the MSI-H phe- changes of p6 bp and type B with insertions or deletions notype.13,14 Furthermore, in several MMR-deficient cell of X8 bp. Tumours were classified as type B if at least one lines with MRE11 biallelic alterations and monoallelic MSI þ marker manifested type B MSI. changes in RAD50 repeat, the significant reduction of both The impairment of the MRE11 and RAD50 gene expres- proteins and corresponding mRNAs were identified. In sions was evaluated by genetic analyses of mononucleotide 15 addition, these cell lines showed an impaired NHEJ. intronic repeats (T)11 within the polypyrimidine stretch/ Moreover, the results of in vitro studies predict that the accessory splicing signal and exonic (A)9 tract, respectively, MRE11 gene could be a functional component of MMR together with immunohistochemical (IHC) analyses of pathway, as the presence of MRE11 mutations increased relevant protein expressions. Insertions or deletions were MSI in both mono- and dinucleotide repeats. Disruption of examined by two methods: fragment analysis and genomic MLH1–MRE11 interactions might represent
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