title: FANCJ suppresses microsatellite instability and lymphomagenesis independent of the Fanconi anemia pathway.
abstract: Microsatellites are short tandem repeat sequences that are highly prone to expansion/contraction due to their propensity to form non-B-form DNA structures, which hinder DNA polymerases and provoke template slippage. Although error correction by mismatch repair plays a key role in preventing microsatellite instability (MSI), which is a hallmark of Lynch syndrome, activities must also exist that unwind secondary structures to facilitate replication fidelity. Here, we report that Fancj helicase-deficient mice, while phenotypically resembling Fanconi anemia (FA), are also hypersensitive to replication inhibitors and predisposed to lymphoma. Whereas metabolism of G4-DNA structures is largely unaffected in Fancj(-/-) mice, high levels of spontaneous MSI occur, which is exacerbated by replication inhibition. In contrast, MSI is not observed in Fancd2(-/-) mice but is prevalent in human FA-J patients. Together, these data implicate FANCJ as a key factor required to counteract MSI, which is functionally distinct from its role in the FA pathway.
authors.affiliation: DNA Damage Response Laboratory, Clare Hall Laboratories, The Francis Crick Institute, South Mimms EN6 3LD, United Kingdom;
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Matsuzaki
authors.affiliation: DNA Damage Response Laboratory, Clare Hall Laboratories, The Francis Crick Institute, South Mimms EN6 3LD, United Kingdom;
authors.forename: Valerie
authors.initials: V
authors.lastname: Borel
authors.affiliation: DNA Damage Response Laboratory, Clare Hall Laboratories, The Francis Crick Institute, South Mimms EN6 3LD, United Kingdom;
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Adelman
authors.affiliation: Department of Human Genetics, Biozentrum, University of Wurzburg, 97074 Wurzburg, Germany.
authors.forename: Detlev
authors.initials: D
authors.lastname: Schindler
authors.affiliation: DNA Damage Response Laboratory, Clare Hall Laboratories, The Francis Crick Institute, South Mimms EN6 3LD, United Kingdom;
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Boulton
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D050976:Basic-Leucine Zipper Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D002166:Camptothecin / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D004249:DNA Damage / Q000235:genetics; D005199:Fanconi Anemia / Q000235:genetics / Q000503:physiopathology*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics; D051856:Fanconi Anemia Complementation Group Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000528:radiation effects; D020022:Genetic Predisposition to Disease; D006801:Humans; D008223:Lymphoma / Q000235:genetics*; D008297:Male; D018345:Mice, Knockout; D053842:Microsatellite Instability; D016685:Mitomycin / Q000494:pharmacology; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics; D020365:RNA Helicases; D014466:Ultraviolet Rays
chemical_list: D000970:Antineoplastic Agents; D050976:Basic-Leucine Zipper Transcription Factors; D052236:Fanconi Anemia Complementation Group D2 Protein; D051856:Fanconi Anemia Complementation Group Proteins; D016685:Mitomycin; C000606761:Brip1 protein, mouse; D020365:RNA Helicases; D002166:Camptothecin
keywords: DNA repair; FANCJ; Fanconi anemia; genome stability; microsatellite instability