PrimPol Bypasses UV Photoproducts during Eukaryotic Chromosomal DNA Replication

Julie Bianchi,Sean G Rudd,Stanislaw K Jozwiakowski,Laura J Bailey,Violetta Soura,Elaine Taylor,Irena Stevanovic,Andrew J Green,Travis H Stracker,Howard D Lindsay,Aidan J Doherty

doi:10.1016/j.molcel.2013.10.035

Julie Bianchi, Sean G Rudd + Show 9 more

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https://doi.org/10.1016/j.molcel.2013.10.035

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SummaryDNA 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.

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DNA damage frequently stalls the DNA replication machinery, and bypass mechanisms exist to ensure complete chromosomal duplication and prevent genome instability (Aguilera and Gomez-Gonzalez, 2008)
We investigate cellular roles of PrimPol and establish that this archaeo-eukaryotic primase (AEP) is required for efficient fork progression during chromosomal DNA replication on both damaged and undamaged templates in higher eukaryotes
To determine if additional AEPs reside in the eukarya, a bioinformatics search was undertaken of the available eukaryotic genomes for genes with homology to AEP-like primases

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Introduction

DNA damage frequently stalls the DNA replication machinery, and bypass mechanisms exist to ensure complete chromosomal duplication and prevent genome instability (Aguilera and Gomez-Gonzalez, 2008). DNA replication can proceed in the presence of damage by convergence of adjacent replicons, discontinuous synthesis of Okazaki fragments on the lagging strand, or repriming of DNA synthesis downstream of lesions on the leading strand (Heller and Marians, 2006; Yeeles and Marians, 2011). These produce singlestranded (ss) DNA gaps behind replication forks that are subsequently filled using TLS or HR (Lopes et al, 2006). We investigate cellular roles of PrimPol and establish that this AEP is required for efficient fork progression during chromosomal DNA replication on both damaged and undamaged templates in higher eukaryotes

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