2. Academic Validation
  3. FANCD2-Associated Nuclease 1 Partially Compensates for the Lack of Exonuclease 1 in Mismatch Repair

FANCD2-Associated Nuclease 1 Partially Compensates for the Lack of Exonuclease 1 in Mismatch Repair

  • Mol Cell Biol. 2021 Aug 24;41(9):e0030321. doi: 10.1128/MCB.00303-21.
Katja Kratz 1,  Mariela Artola-Borán 1,  Saho Kobayashi-Era 1 2,  Gene Koh 3 4 5,  Goncalo Oliveira 6,  Shunsuke Kobayashi 1 2,  Andreia Oliveira 1 2,  Xueqing Zou 3 4 5,  Julia Richter 2,  Masataka Tsuda 7,  Hiroyuki Sasanuma 7,  Shunichi Takeda 7,  Joanna I Loizou 6,  Alessandro A Sartori 1,  Serena Nik-Zainal 4 5,  Josef Jiricny 1 2
Affiliations

Affiliations

  • 1 Institute of Molecular Cancer Research, University of Zurichgrid.7400.3, Zurich, Switzerland.
  • 2 Institute of Biochemistry of the ETH Zurichgrid.5801.c, Zurich, Switzerland.
  • 3 Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom.
  • 4 Academic Department of Medical Genetics, The Clinical School, University of Cambridgegrid.5335.0, Cambridge, United Kingdom.
  • 5 MRC Cancer Unit, The Clinical School, University of Cambridgegrid.5335.0, Cambridge, United Kingdom.
  • 6 Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Centre, Medical University of Viennagrid.22937.3d, Vienna, Austria.
  • 7 Department of Radiation Genetics, Graduate School of Medicine, Kyoto Universitygrid.258799.8, Kyoto, Japan.
PMID: 34228493 DOI: 10.1128/MCB.00303-21
Abstract

Germline mutations in the mismatch repair (MMR) genes MSH2, MSH6, MLH1, and PMS2 are linked to Cancer of the colon and Other organs, characterized by microsatellite instability and a large increase in mutation frequency. Unexpectedly, mutations in EXO1, encoding the only exonuclease genetically implicated in MMR, are not linked to familial Cancer and cause a substantially weaker mutator phenotype. This difference could be explained if eukaryotic cells possessed additional exonucleases redundant with EXO1. Analysis of the MLH1 interactome identified FANCD2-associated nuclease 1 (FAN1), a novel Enzyme with biochemical properties resembling EXO1. We now show that FAN1 efficiently substitutes for EXO1 in MMR assays and that this functional complementation is modulated by its interaction with MLH1. FAN1 also contributes to MMR in vivo; cells lacking both EXO1 and FAN1 have an MMR defect and display resistance to N-methyl-N-nitrosourea (MNU) and 6-thioguanine (TG). Moreover, FAN1 loss amplifies the mutational profile of EXO1-deficient cells, suggesting that the two nucleases act redundantly in the same antimutagenic pathway. However, the increased drug resistance and mutator phenotype of FAN1/EXO1-deficient cells are less prominent than those seen in cells lacking MSH6 or MLH1. Eukaryotic cells thus apparently possess additional mechanisms that compensate for the loss of EXO1.

Keywords

DNA repair; EXO1; FAN1; MLH1; MSH6; exonuclease; mismatch repair; mutational signature.

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