title: PrimPol prevents APOBEC/AID family mediated DNA mutagenesis.
abstract: PrimPol is a DNA damage tolerant polymerase displaying both translesion synthesis (TLS) and (re)-priming properties. This led us to study the consequences of a PrimPol deficiency in tolerating mutagenic lesions induced by members of the APOBEC/AID family of cytosine deaminases. Interestingly, during somatic hypermutation, PrimPol counteracts the generation of C>G transversions on the leading strand. Independently, mutation analyses in human invasive breast cancer confirmed a pro-mutagenic activity of APOBEC3B and revealed a genome-wide anti-mutagenic activity of PRIMPOL as well as most Y-family TLS polymerases. PRIMPOL especially prevents APOBEC3B targeted cytosine mutations within TpC dinucleotides. As C transversions induced by APOBEC/AID family members depend on the formation of AP-sites, we propose that PrimPol reprimes preferentially downstream of AP-sites on the leading strand, to prohibit error-prone TLS and simultaneously stimulate error-free homology directed repair. These in vivo studies are the first demonstrating a critical anti-mutagenic activity of PrimPol in genome maintenance.
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Bas
authors.initials: B
authors.lastname: Pilzecker
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Olimpia Alessandra
authors.initials: OA
authors.lastname: Buoninfante
authors.affiliation: Mouse Clinic for Cancer and Aging research (MCCA) Transgenic Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Colin
authors.initials: C
authors.lastname: Pritchard
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Olga S
authors.initials: OS
authors.lastname: Blomberg
authors.affiliation: Mouse Clinic for Cancer and Aging research (MCCA) Transgenic Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Ivo J
authors.initials: IJ
authors.lastname: Huijbers
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Paul C M
authors.initials: PC
authors.lastname: van den Berk
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands h.jacobs@nki.nl.
authors.forename: Heinz
authors.initials: H
authors.lastname: Jacobs
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics; D064113:CRISPR-Cas Systems; D002460:Cell Line; D002470:Cell Survival / Q000528:radiation effects; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D019915:DNA Primase / Q000502:physiology*; D004261:DNA Replication; D004259:DNA-Directed DNA Polymerase / Q000502:physiology*; D005260:Female; D006801:Humans; D017578:Immunoglobulin Class Switching; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens / Q000378:metabolism*; D064251:Multifunctional Enzymes / Q000502:physiology*; D016296:Mutagenesis; D027041:Somatic Hypermutation, Immunoglobulin; D013601:T-Lymphocytes / Q000201:enzymology; D014466:Ultraviolet Rays
chemical_list: D015778:Minor Histocompatibility Antigens; D064251:Multifunctional Enzymes; D004247:DNA; D019915:DNA Primase; C585901:PrimPol protein, human; D004259:DNA-Directed DNA Polymerase; C495794:APOBEC3B protein, human; D003564:Cytidine Deaminase