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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Vydáno v:	Nucleic acids research Ročník 44; číslo 10; s. 4734 - 4744
Hlavní autoři:	Pilzecker, Bas, Buoninfante, Olimpia Alessandra, Pritchard, Colin, Blomberg, Olga S., Huijbers, Ivo J., van den Berk, Paul C.M., Jacobs, Heinz
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	England Oxford University Press 02.06.2016
Témata:	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
ISSN:	0305-1048, 1362-4962
On-line přístup:	Získat plný text
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0305-1048 1362-4962
DOI:	10.1093/nar/gkw123