title: Roles of human POLD1 and POLD3 in genome stability.
abstract: DNA replication is essential for cellular proliferation. If improperly controlled it can constitute a major source of genome instability, frequently associated with cancer and aging. POLD1 is the catalytic subunit and POLD3 is an accessory subunit of the replicative Pol δ polymerase, which also functions in DNA repair, as well as the translesion synthesis polymerase Pol ζ, whose catalytic subunit is REV3L. In cells depleted of POLD1 or POLD3 we found a differential but general increase in genome instability as manifested by DNA breaks, S-phase progression impairment and chromosome abnormalities. Importantly, we showed that both proteins are needed to maintain the proper amount of active replication origins and that POLD3-depletion causes anaphase bridges accumulation. In addition, POLD3-associated DNA damage showed to be dependent on RNA-DNA hybrids pointing toward an additional and specific role of this subunit in genome stability. Interestingly, a similar increase in RNA-DNA hybrids-dependent genome instability was observed in REV3L-depleted cells. Our findings demonstrate a key role of POLD1 and POLD3 in genome stability and S-phase progression revealing RNA-DNA hybrids-dependent effects for POLD3 that might be partly due to its Pol ζ interaction.
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla, Avd. Américo Vespucio s/n, 41092 Seville, Spain.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Tumini
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla, Avd. Américo Vespucio s/n, 41092 Seville, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Barroso
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla, Avd. Américo Vespucio s/n, 41092 Seville, Spain.
authors.forename: Carmen Pérez
authors.initials: CP
authors.lastname: -Calero
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla, Avd. Américo Vespucio s/n, 41092 Seville, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Aguilera
mesh_terms: D053960:DNA Breaks; D004258:DNA Polymerase III / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication; D042822:Genomic Instability; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D009692:Nucleic Acid Heteroduplexes / Q000235:genetics / Q000378:metabolism; D016196:S Phase
chemical_list: D009692:Nucleic Acid Heteroduplexes; C434055:POLD1 protein, human; C435720:POLD3 protein, human; D004258:DNA Polymerase III