DNA replication stress mediates APOBEC3 family mutagenesis in breast cancer

BackgroundThe APOBEC3 family of cytidine deaminases mutate the cancer genome in a range of cancer types. Although many studies have documented the downstream effects of APOBEC3 activity through next-generation sequencing, less is known about their upstream regulation. In this study, we sought to identify a molecular basis for APOBEC3 expression and activation.ResultsHER2 amplification and PTEN loss promote DNA replication stress and APOBEC3B activity in vitro and correlate with APOBEC3 mutagenesis in vivo. HER2-enriched breast carcinomas display evidence of elevated levels of replication stress-associated DNA damage in vivo. Chemical and cytotoxic induction of replication stress, through aphidicolin, gemcitabine, camptothecin or hydroxyurea exposure, activates transcription of APOBEC3B via an ATR/Chk1-dependent pathway in vitro. APOBEC3B activation can be attenuated through repression of oncogenic signalling, small molecule inhibition of receptor tyrosine kinase signalling and alleviation of replication stress through nucleoside supplementation.ConclusionThese data link oncogene, loss of tumour suppressor gene and drug-induced replication stress with APOBEC3B activity, providing new insights into how cytidine deaminase-induced mutagenesis might be activated in tumourigenesis and limited therapeutically.

[1]  W. Plunkett,et al.  Mechanisms of apoptosis induction by nucleoside analogs , 2003, Oncogene.

[2]  M. Marin,et al.  Transcriptional Regulation of APOBEC3G, a Cytidine Deaminase That Hypermutates Human Immunodeficiency Virus* , 2004, Journal of Biological Chemistry.

[3]  T. Ørntoft,et al.  DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis , 2005, Nature.

[4]  J. Bartek,et al.  Inhibition of Human Chk1 Causes Increased Initiation of DNA Replication, Phosphorylation of ATR Targets, and DNA Breakage , 2005, Molecular and Cellular Biology.

[5]  M. Khan,et al.  Monomeric APOBEC3G Is Catalytically Active and Has Antiviral Activity , 2006, Journal of Virology.

[6]  Dimitris Kletsas,et al.  Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints , 2006, Nature.

[7]  Takeshi Azuma,et al.  Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium , 2007, Nature Medicine.

[8]  M. Moasser.  The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis , 2007, Oncogene.

[9]  A. Rustgi,et al.  Nuclear accumulation of cyclin D1 during S phase inhibits Cul4-dependent Cdt1 proteolysis and triggers p53-dependent DNA rereplication. , 2007, Genes & development.

[10]  A. Nobel,et al.  Supervised risk predictor of breast cancer based on intrinsic subtypes. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  P. Jeggo,et al.  The role of homologous recombination in radiation-induced double-strand break repair. , 2011, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[12]  B. Neumann,et al.  53BP1 nuclear bodies form around DNA lesions generated by mitotic transmission of chromosomes under replication stress , 2011, Nature Cell Biology.

[13]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[14]  B. Kerem,et al.  Nucleotide Deficiency Promotes Genomic Instability in Early Stages of Cancer Development , 2011, Cell.

[15]  Lela Lackey,et al.  Human and Rhesus APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H Demonstrate a Conserved Capacity To Restrict Vif-Deficient HIV-1 , 2011, Journal of Virology.

[16]  J. Manley,et al.  R-loop-mediated genomic instability is caused by impairment of replication fork progression. , 2011, Genes & development.

[17]  S. Robinson,et al.  CCT244747 Is a Novel Potent and Selective CHK1 Inhibitor with Oral Efficacy Alone and in Combination with Genotoxic Anticancer Drugs , 2012, Clinical Cancer Research.

[18]  Steven A. Roberts,et al.  Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions. , 2012, Molecular cell.

[19]  I. Willner,et al.  APOBEC3G enhances lymphoma cell radioresistance by promoting cytidine deaminase-dependent DNA repair. , 2012, Blood.

[20]  A. Børresen-Dale,et al.  Mutational Processes Molding the Genomes of 21 Breast Cancers , 2012, Cell.

[21]  Steven A. Roberts,et al.  An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers , 2013, Nature Genetics.

[22]  Julian Downward,et al.  Coordinate direct input of both KRAS and IGF1 receptor to activation of PI3 kinase in KRAS-mutant lung cancer. , 2013, Cancer discovery.

[23]  David T. W. Jones,et al.  Signatures of mutational processes in human cancer , 2013, Nature.

[24]  K. Cimprich,et al.  Causes and consequences of replication stress , 2013, Nature Cell Biology.

[25]  Jiri Bartek,et al.  Replication stress links structural and numerical cancer chromosomal instability , 2013, Nature.

[26]  Replication stress links structural and numerical cancer chromosomal instability (vol 494, pg 492, 2013) , 2013 .

[27]  N. McGranahan,et al.  The causes and consequences of genetic heterogeneity in cancer evolution , 2013, Nature.

[28]  Lela Lackey,et al.  Subcellular localization of the APOBEC3 proteins during mitosis and implications for genomic DNA deamination , 2013, Cell cycle.

[29]  N. A. Temiz,et al.  Evidence for APOBEC3B mutagenesis in multiple human cancers , 2013, Nature Genetics.

[30]  N. A. Temiz,et al.  APOBEC3B is an enzymatic source of mutation in breast cancer , 2013, Nature.

[31]  Lela Lackey,et al.  Endogenous APOBEC3A DNA Cytosine Deaminase Is Cytoplasmic and Nongenotoxic* , 2013, The Journal of Biological Chemistry.

[32]  M. Stratton,et al.  DNA deaminases induce break-associated mutation showers with implication of APOBEC3B and 3A in breast cancer kataegis , 2013, eLife.

[33]  J. Diffley,et al.  DNA Replication and Oncogene-Induced Replicative Stress , 2014, Current Biology.

[34]  Charles Swanton,et al.  Cancer: evolution within a lifetime. , 2014, Annual review of genetics.

[35]  S. Henderson,et al.  APOBEC-mediated cytosine deamination links PIK3CA helical domain mutations to human papillomavirus-driven tumor development. , 2014, Cell reports.

[36]  Z. Szallasi,et al.  Spatial and temporal diversity in genomic instability processes defines lung cancer evolution , 2014, Science.

[37]  Cynthia J. Sakofsky,et al.  Break-induced replication is a source of mutation clusters underlying kataegis. , 2014, Cell reports.

[38]  Steven J. M. Jones,et al.  Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer , 2015, Cell.

[39]  A. Aguilera,et al.  Replication stress and cancer , 2015, Nature Reviews Cancer.

[40]  R. Gelber,et al.  Tailoring therapies—improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015 , 2015, Annals of oncology : official journal of the European Society for Medical Oncology.

[41]  Nicolai J. Birkbak,et al.  Clonal status of actionable driver events and the timing of mutational processes in cancer evolution , 2015, Science Translational Medicine.

[42]  Peter J. Campbell,et al.  Chromothripsis and Kataegis Induced by Telomere Crisis , 2015, Cell.

[43]  Jiri Bartek,et al.  Myc and Ras oncogenes engage different energy metabolism programs and evoke distinct patterns of oxidative and DNA replication stress , 2014, Molecular oncology.

[44]  Z. Szallasi,et al.  SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair , 2015, Oncogene.

[45]  Rebecca M. McDougle,et al.  The PKC/NF-κB signaling pathway induces APOBEC3B expression in multiple human cancers. , 2015, Cancer research.

[46]  C. Swanton,et al.  RAD18, WRNIP1 and ATMIN promote ATM signalling in response to replication stress , 2015, Oncogene.

[47]  M. Walton,et al.  The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eμ-MYC driven B-cell lymphoma , 2015, Oncotarget.

[48]  P. Mieczkowski,et al.  APOBEC3A and APOBEC3B Preferentially Deaminate the Lagging Strand Template during DNA Replication. , 2016, Cell reports.

[49]  Jan O. Korbel,et al.  Negative Selection and Chromosome Instability Induced by Mad2 Overexpression Delay Breast Cancer but Facilitate Oncogene-Independent Outgrowth , 2016, Cell reports.

[50]  B. Taylor,et al.  deconstructSigs: delineating mutational processes in single tumors distinguishes DNA repair deficiencies and patterns of carcinoma evolution , 2016, Genome Biology.