Human MRE11 is Inactivated in Mismatch Repair-deficient Cancers

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2002 Feb 19

PMID 11850399

Citations 85

Authors

Giuseppe Giannini

Elisabetta Ristori

Fabio Cerignoli

Christian Rinaldi

Massimo Zani

Alessandra Viel

Laura Ottini

Marco Crescenzi

Stefano Martinotti

Margherita Bignami

Luigi Frati

Isabella Screpanti

Alberto Gulino

Affiliations

Soon will be listed here.

Abstract

Mutations of the ATM and NBS1 genes are responsible for the inherited Ataxia-Telangiectasia and Nijmegen Breakage Syndrome, both of which are associated with a predisposition to cancer. A related syndrome, the Ataxia-Telangiectasia-like disorder, is due to mutations of the MRE11 gene. However, the role of this gene in cancer development has not been established. Here we describe an often homozygous mutation of the poly(T)11 repeat within human MRE11 intron 4 that leads to aberrant splicing, impairment of wild-type MRE11 expression and generation of a truncated protein. This mutation is present in mismatch repair-deficient, but not proficient, colorectal cancer cell lines and primary tumours and is associated with reduced expression of the MRE11--NBS1--RAD50 complex, an impaired S-phase checkpoint and abrogation of MRE11 and NBS1 ionizing radiation-induced nuclear foci. Our findings identify MRE11 as a novel and major target for inactivation in mismatch repair-defective cells and suggest its impairment may contribute to the development of colorectal cancer.

Citing Articles

Targeting PARP-1 and DNA Damage Response Defects in Colorectal Cancer Chemotherapy with Established and Novel PARP Inhibitors.

Demuth P, Thibol L, Lemsch A, Potlitz F, Schulig L, Grathwol C Cancers (Basel). 2024; 16(20).

PMID: 39456536 PMC: 11506018. DOI: 10.3390/cancers16203441.

Small molecule targeted therapies for endometrial cancer: progress, challenges, and opportunities.

Yang F, Zhao T, Milaneh S, Zhang C, Xiang D, Wang W RSC Med Chem. 2024; 15(6):1828-1848.

PMID: 38911148 PMC: 11187550. DOI: 10.1039/d4md00089g.

MRE11A: a novel negative regulator of human DNA mismatch repair.

Du D, Yang Y, Zhang Y, Wang G, Chen L, Guan X Cell Mol Biol Lett. 2024; 29(1):37.

PMID: 38486171 PMC: 10938699. DOI: 10.1186/s11658-024-00547-z.

RAD51 restricts DNA over-replication from re-activated origins.

Munoz S, Blanco-Romero E, Gonzalez-Acosta D, Rodriguez-Acebes S, Megias D, Lopes M EMBO J. 2024; 43(6):1043-1064.

PMID: 38360996 PMC: 10942984. DOI: 10.1038/s44318-024-00038-z.

Metabolic regulation of homologous recombination repair by MRE11 lactylation.

Chen Y, Wu J, Zhai L, Zhang T, Yin H, Gao H Cell. 2023; 187(2):294-311.e21.

PMID: 38128537 PMC: 11725302. DOI: 10.1016/j.cell.2023.11.022.

References

Thibodeau S, Bren G, Schaid D . Microsatellite instability in cancer of the proximal colon. Science. 1993; 260(5109):816-9. DOI: 10.1126/science.8484122. View

Haber J . The many interfaces of Mre11. Cell. 1998; 95(5):583-6. DOI: 10.1016/s0092-8674(00)81626-8. View

Varon R, Reis A, Henze G, von Einsiedel H, Sperling K, Seeger K . Mutations in the Nijmegen Breakage Syndrome gene (NBS1) in childhood acute lymphoblastic leukemia (ALL). Cancer Res. 2001; 61(9):3570-2. View

Petrini J . The Mre11 complex and ATM: collaborating to navigate S phase. Curr Opin Cell Biol. 2000; 12(3):293-6. DOI: 10.1016/s0955-0674(00)00091-0. View

Xiao Y, Weaver D . Conditional gene targeted deletion by Cre recombinase demonstrates the requirement for the double-strand break repair Mre11 protein in murine embryonic stem cells. Nucleic Acids Res. 1997; 25(15):2985-91. PMC: 146850. DOI: 10.1093/nar/25.15.2985. View

Viel A, Genuardi M, Capozzi E, Leonardi F, Bellacosa A, Pomponi M . Characterization of MSH2 and MLH1 mutations in Italian families with hereditary nonpolyposis colorectal cancer. Genes Chromosomes Cancer. 1997; 18(1):8-18. DOI: 10.1002/(sici)1098-2264(199701)18:1<8::aid-gcc2>3.0.co;2-7. View

Schaffner C, Idler I, Stilgenbauer S, Dohner H, Lichter P . Mantle cell lymphoma is characterized by inactivation of the ATM gene. Proc Natl Acad Sci U S A. 2000; 97(6):2773-8. PMC: 16005. DOI: 10.1073/pnas.050400997. View

Ionov Y, Peinado M, Malkhosyan S, Shibata D, Perucho M . Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature. 1993; 363(6429):558-61. DOI: 10.1038/363558a0. View

Aaltonen L, Peltomaki P, Leach F, Sistonen P, Pylkkanen L, Mecklin J . Clues to the pathogenesis of familial colorectal cancer. Science. 1993; 260(5109):812-6. DOI: 10.1126/science.8484121. View

10.

BELL D, Varley J, Szydlo T, Kang D, Wahrer D, Shannon K . Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 2000; 286(5449):2528-31. DOI: 10.1126/science.286.5449.2528. View

11.

Stankovic T, Weber P, Stewart G, Bedenham T, Murray J, Byrd P . Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia. Lancet. 1999; 353(9146):26-9. DOI: 10.1016/S0140-6736(98)10117-4. View

12.

Kim N, Choi Y, Baek M, Kim Y, Kang H, Kim N . Frameshift mutations at coding mononucleotide repeats of the hRAD50 gene in gastrointestinal carcinomas with microsatellite instability. Cancer Res. 2001; 61(1):36-8. View

13.

Pitts S, Kullar H, Stankovic T, Stewart G, Last J, Bedenham T . hMRE11: genomic structure and a null mutation identified in a transcript protected from nonsense-mediated mRNA decay. Hum Mol Genet. 2001; 10(11):1155-62. DOI: 10.1093/hmg/10.11.1155. View

14.

Gatei M, Young D, Cerosaletti K, Spring K, Kozlov S, Lavin M . ATM-dependent phosphorylation of nibrin in response to radiation exposure. Nat Genet. 2000; 25(1):115-9. DOI: 10.1038/75508. View

15.

Fukuda T, Sumiyoshi T, Takahashi M, Kataoka T, Asahara T, Inui H . Alterations of the double-strand break repair gene MRE11 in cancer. Cancer Res. 2001; 61(1):23-6. View

16.

Khanna K, Jackson S . DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet. 2001; 27(3):247-54. DOI: 10.1038/85798. View

17.

Coolidge C, Seely R, Patton J . Functional analysis of the polypyrimidine tract in pre-mRNA splicing. Nucleic Acids Res. 1997; 25(4):888-96. PMC: 146492. DOI: 10.1093/nar/25.4.888. View

18.

Nelms B, Maser R, Mackay J, Lagally M, Petrini J . In situ visualization of DNA double-strand break repair in human fibroblasts. Science. 1998; 280(5363):590-2. DOI: 10.1126/science.280.5363.590. View

19.

Xu B, Kim St , Kastan M . Involvement of Brca1 in S-phase and G(2)-phase checkpoints after ionizing irradiation. Mol Cell Biol. 2001; 21(10):3445-50. PMC: 100266. DOI: 10.1128/MCB.21.10.3445-3450.2001. View

20.

Grenon M, Gilbert C, Lowndes N . Checkpoint activation in response to double-strand breaks requires the Mre11/Rad50/Xrs2 complex. Nat Cell Biol. 2001; 3(9):844-7. DOI: 10.1038/ncb0901-844. View