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Martin S.A.,Cancer Research UK Gene Function and Regulation Group | Martin S.A.,Institute of Cancer Research | Lord C.J.,Institute of Cancer Research | Ashworth A.,Cancer Research UK Gene Function and Regulation Group | Ashworth A.,Institute of Cancer Research
Clinical Cancer Research | Year: 2010

The mismatch repair (MMR) pathway is involved in the removal of DNA base mismatches that arise either during DNA replication or are caused by DNA damage. Mutations in four genes involved in MMR, MSH2, MLH1, PMS2 and MSH6, predispose to a range of tumorigenic conditions, including hereditary nonpolyposis colon cancer, also known as Lynch syndrome. Here we discuss the canonical MMR pathway and the burgeoning evidence for noncanonical roles for the MMR genes, and highlight the therapeutic implications of MMR. In particular, we discuss how the DNA repair defect in MMR-deficient cancers could be exploited by the development of novel therapeutic strategies based on synthetic lethal approaches. ©2010 AACR. Source

Brough R.,Cancer Research UK Gene Function and Regulation Group | Brough R.,Institute of Cancer Research | Bajrami I.,Cancer Research UK Gene Function and Regulation Group | Bajrami I.,Institute of Cancer Research | And 6 more authors.
EMBO Journal | Year: 2012

Mutations in BRCA2 confer an increased risk of cancer development, at least in part because the BRCA2 protein is required for the maintenance of genomic integrity. Here, we use proteomic profiling to identify APRIN (PDS5B), a cohesion-associated protein, as a BRCA2-associated protein. After exposure of cells to hydroxyurea or aphidicolin, APRIN and other cohesin components associate with BRCA2 in early S-phase. We demonstrate that APRIN expression is required for the normal response to DNA-damaging agents, the nuclear localisation of RAD51 and BRCA2 and efficient homologous recombination. The clinical significance of these findings is indicated by the observation that the BRCA2/APRIN interaction is compromised by BRCA2 missense variants of previously unknown significance and that APRIN expression levels are associated with histological grade in breast cancer and the outcome of breast cancer patients treated with DNA-damaging chemotherapy. © 2012 European Molecular Biology Organization | All Rights Reserved. Source

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