PrimPol prevents APOBEC/AID family mediated DNA mutagenesis

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...

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Bibliographic Details
Published in:Nucleic acids research 2016-06, Vol.44 (10), p.4734-4744
Main Authors: Pilzecker, Bas, Buoninfante, Olimpia Alessandra, Pritchard, Colin, Blomberg, Olga S, Huijbers, Ivo J, van den Berk, Paul C M, Jacobs, Heinz
Format: Article
Language:English
Subjects:
Animals
B-Lymphocytes - enzymology
Breast Neoplasms - enzymology
Breast Neoplasms - genetics
Cell Line
Cell Survival - radiation effects
Cells, Cultured
CRISPR-Cas Systems
Cytidine Deaminase - antagonists & inhibitors
Cytidine Deaminase - metabolism
DNA - metabolism
DNA Primase - physiology
DNA Replication
DNA-Directed DNA Polymerase - physiology
Female
Genome Integrity, Repair and
Humans
Immunoglobulin Class Switching
Mice, Inbred C57BL
Minor Histocompatibility Antigens - metabolism
Multifunctional Enzymes - physiology
Mutagenesis
Somatic Hypermutation, Immunoglobulin
T-Lymphocytes - enzymology
Ultraviolet Rays
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Summary: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.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkw123