Repriming of DNA synthesis at stalled replication forks by human PrimPol.
DNA replication forks that collapse during the process of genomic duplication lead to double-strand breaks and constitute a threat to genomic stability. The risk of fork collapse is higher in the presence of replication inhibitors or after UV irradiation, which introduces specific modifications in the structure of DNA. In these cases, fork progression may be facilitated by error-prone translesion synthesis (TLS) DNA polymerases. Alternatively, the replisome may skip the damaged DNA, leaving an unreplicated gap to be repaired after replication. This mechanism strictly requires a priming event downstream of the lesion. Here we show that PrimPol, a new human primase and TLS polymerase, uses its primase activity to mediate uninterrupted fork progression after UV irradiation and to reinitiate DNA synthesis after dNTP depletion. As an enzyme involved in tolerance to DNA damage, PrimPol might become a target for cancer therapy.
Molecular Oncology Program, Spanish National Cancer Research Centre, Madrid, Spain.
Silvana
S
Mourón
Sara
S
Rodriguez-Acebes
María I
MI
Martínez-Jiménez
Sara
S
García-Gómez
Sandra
S
Chocrón
Luis
L
Blanco
Juan
J
Méndez
D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D019915:DNA Primase / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D004261:DNA Replication / Q000502:physiology*; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D042822:Genomic Instability; D006801:Humans; D064251:Multifunctional Enzymes / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D016196:S Phase; D014466:Ultraviolet Rays
D064251:Multifunctional Enzymes; D012333:RNA, Messenger; D019915:DNA Primase; C585901:PrimPol protein, human; D004259:DNA-Directed DNA Polymerase