FHIT loss-induced DNA damage creates optimal APOBEC substrates: Insights into APOBEC-mediated mutagenesis.
APOBEC cytidine deaminase activity is a major source of hypermutation in cancer. But previous studies have shown that the TC context signature of these enzymes is not observed in sizable fractions of cancers with overexpression of APOBEC, suggesting that cooperating factors that contribute to this mutagenesis should be identified. The fragile histidine triad protein (Fhit) is a tumor suppressor and DNA caretaker that is deleted or silenced in >50% of cancers. Loss of Fhit protein activity causes replication stress through reduced Thymidine Kinase 1 expression, increased DNA breaks, and global genome instability in normal and cancer cells. Using data from The Cancer Genome Atlas (TCGA), we show that FHIT-low/APOBEC3B-high expressing lung adenocarcinomas display significantly increased numbers of APOBEC signature mutations. Tumor samples in this cohort with normal FHIT expression do not exhibit APOBEC hypermutation, despite having high APOBEC3B expression. In vitro, silencing Fhit expression elevates APOBEC3B-directed C > T mutations in the TP53 gene. Furthermore, inhibition of Fhit loss-induced DNA damage via thymidine supplementation decreases the TP53 mutation burden in FHIT-low/APOBEC3B-high cells. We conclude that APOBEC3B overexpression and Fhit-loss induced DNA damage are independent events that, when occurring together, result in a significantly increased frequency of APOBEC-induced mutations that drive cancer progression.
Biomedical Sciences Graduate Program, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.|Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Catherine E
CE
Waters
Department of Chemical and Systems Biology, Stanford University School of Medicine, Standford, California, USA.
Joshua C
JC
Saldivar
Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Zaynab A
ZA
Amin
Biomedical Sciences Graduate Program, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.|Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Morgan S
MS
Schrock
Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Kay
K
Huebner
D017766:Acid Anhydride Hydrolases / Q000235:genetics* / Q000378:metabolism; D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D030541:Databases, Genetic; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D015778:Minor Histocompatibility Antigens; D016296:Mutagenesis; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000074584:WW Domain-Containing Oxidoreductase; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D003564:Cytidine Deaminase; D015778:Minor Histocompatibility Antigens; D009363:Neoplasm Proteins; D010088:Oxidoreductases; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000074584:WW Domain-Containing Oxidoreductase; D000099170:Bis(5'-adenosyl)triphosphatase; C495901:TP53 protein, human; C486071:WWOX protein, human; C495794:APOBEC3B protein, human