Alternative solutions and new scenarios for translesion DNA synthesis by human PrimPol.
PrimPol is a recently described DNA polymerase that has the virtue of initiating DNA synthesis. In addition of being a sensu stricto DNA primase, PrimPol's polymerase activity has a large capacity to tolerate different kind of lesions. The different strategies used by PrimPol for DNA damage tolerance are based on its capacity to "read" certain lesions, to skip unreadable lesions, and as an ultimate solution, to restart DNA synthesis beyond the lesion thus acting as a TLS primase. This lesion bypass potential, revised in this article, is strengthened by the preferential use of moderate concentrations of manganese ions as the preferred metal activator. We show here that PrimPol is able to extend RNA primers with ribonucleotides, even when bypassing 8oxoG lesions, suggesting a potential new scenario for PrimPol as a TLS polymerase assisting transcription. We also show that PrimPol displays a high degree of versatility to accept or induce distortions of both primer and template strands, creating alternative alignments based on microhomology that would serve to skip unreadable lesions and to connect separate strands. In good agreement, PrimPol is highly prone to generate indels at short nucleotide repeats. Finally, an evolutionary view of the relationship between translesion synthesis and primase functions is briefly discussed.
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid 28049, Spain.
María I
MI
Martínez-Jiménez
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid 28049, Spain.
Sara
S
García-Gómez
Genome Integrity and Structural Biology Laboratory, National Institutes of Health, Research Triangle Park, NC 27709, United States.
Katarzyna
K
Bebenek
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid 28049, Spain.
Guillermo
G
Sastre-Moreno
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid 28049, Spain.
Patricia A
PA
Calvo
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid 28049, Spain.
Alberto
A
Díaz-Talavera
Genome Integrity and Structural Biology Laboratory, National Institutes of Health, Research Triangle Park, NC 27709, United States.
Thomas A
TA
Kunkel
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid 28049, Spain. Electronic address: lblanco@cbm.csic.es.
Luis
L
Blanco
D002412:Cations; D004247:DNA / Q000096:biosynthesis / Q000378:metabolism*; D004249:DNA Damage; D019915:DNA Primase / Q000737:chemistry / Q000378:metabolism*; D004260:DNA Repair; D004261:DNA Replication; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008345:Manganese / Q000737:chemistry; D064251:Multifunctional Enzymes / Q000737:chemistry / Q000378:metabolism*; D009690:Nucleic Acid Conformation
D002412:Cations; D064251:Multifunctional Enzymes; D008345:Manganese; D004247:DNA; D019915:DNA Primase; C585901:PrimPol protein, human; D004259:DNA-Directed DNA Polymerase
8oxoG; DNA polymerase; DNA primase; Lesion bypass; PrimPol; Translesion synthesis