title: PrimPol bypasses UV photoproducts during eukaryotic chromosomal DNA replication.
abstract: DNA damage can stall the DNA replication machinery, leading to genomic instability. Thus, numerous mechanisms exist to complete genome duplication in the absence of a pristine DNA template, but identification of the enzymes involved remains incomplete. Here, we establish that Primase-Polymerase (PrimPol; CCDC111), an archaeal-eukaryotic primase (AEP) in eukaryotic cells, is involved in chromosomal DNA replication. PrimPol is required for replication fork progression on ultraviolet (UV) light-damaged DNA templates, possibly mediated by its ability to catalyze translesion synthesis (TLS) of these lesions. This PrimPol UV lesion bypass pathway is not epistatic with the Pol η-dependent pathway and, as a consequence, protects xeroderma pigmentosum variant (XP-V) patient cells from UV-induced cytotoxicity. In addition, we establish that PrimPol is also required for efficient replication fork progression during an unperturbed S phase. These and other findings indicate that PrimPol is an important player in replication fork progression in eukaryotic cells.
authors.affiliation: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton BN1 9RQ, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Bianchi
authors.forename: Sean G
authors.initials: SG
authors.lastname: Rudd
authors.forename: Stanislaw K
authors.initials: SK
authors.lastname: Jozwiakowski
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Bailey
authors.forename: Violetta
authors.initials: V
authors.lastname: Soura
authors.forename: Elaine
authors.initials: E
authors.lastname: Taylor
authors.forename: Irena
authors.initials: I
authors.lastname: Stevanovic
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Green
authors.forename: Travis H
authors.initials: TH
authors.lastname: Stracker
authors.forename: Howard D
authors.initials: HD
authors.lastname: Lindsay
authors.forename: Aidan J
authors.initials: AJ
authors.lastname: Doherty
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D002645:Chickens; D002877:Chromosomes, Human / Q000235:genetics*; D018736:DNA Adducts / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D019915:DNA Primase / Q000737:chemistry / Q000502:physiology*; D004261:DNA Replication; D004277:DNA, Single-Stranded / Q000737:chemistry; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000502:physiology*; D059565:G2 Phase Cell Cycle Checkpoints; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D064251:Multifunctional Enzymes / Q000737:chemistry / Q000502:physiology*; D014466:Ultraviolet Rays; D014981:Xenopus
chemical_list: D018736:DNA Adducts; D004277:DNA, Single-Stranded; D064251:Multifunctional Enzymes; D019915:DNA Primase; C585901:PrimPol protein, human; D004259:DNA-Directed DNA Polymerase