Pfh1 Is an Accessory Replicative Helicase that Interacts with the Replisome to Facilitate Fork Progression and Preserve Genome Integrity

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McDonald, Karin R. (author)

Pfh1 Is an Accessory Replicative Helicase that Interacts with the Replisome to Facilitate Fork Progression and Preserve Genome Integrity

Article/chapterEnglish2016

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2016-09-09
Copernicus GmbH,2016
electronicrdacarrier

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LIBRIS-ID:oai:DiVA.org:umu-125854
https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-125854URI
https://doi.org/10.1371/journal.pgen.1006238DOI

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Language:English
Summary in:English

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Subject category:art swepub-publicationtype

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Replicative DNA helicases expose the two strands of the double helix to the replication apparatus, but accessory helicases are often needed to help forks move past naturally occurring hard-to-replicate sites, such as tightly bound proteins, RNA/DNA hybrids, and DNA secondary structures. Although the Schizosaccharomyces pombe 5'-to-3' DNA helicase Pfh1 is known to promote fork progression, its genomic targets, dynamics, and mechanisms of action are largely unknown. Here we address these questions by integrating genome-wide identification of Pfh1 binding sites, comprehensive analysis of the effects of Pfh1 depletion on replication and DNA damage, and proteomic analysis of Pfh1 interaction partners by immunoaffinity purification mass spectrometry. Of the 621 high confidence Pfh1-binding sites in wild type cells, about 40% were sites of fork slowing (as marked by high DNA polymerase occupancy) and/or DNA damage (as marked by high levels of phosphorylated H2A). The replication and integrity of tRNA and 5S rRNA genes, highly transcribed RNA polymerase II genes, and nucleosome depleted regions were particularly Pfh1-dependent. The association of Pfh1 with genomic integrity at highly transcribed genes was S phase dependent, and thus unlikely to be an artifact of high transcription rates. Although Pfh1 affected replication and suppressed DNA damage at discrete sites throughout the genome, Pfh1 and the replicative DNA polymerase bound to similar extents to both Pfh1-dependent and independent sites, suggesting that Pfh1 is proximal to the replication machinery during S phase. Consistent with this interpretation, Pfh1 co-purified with many key replisome components, including the hexameric MCM helicase, replicative DNA polymerases, RPA, and the processivity clamp PCNA in an S phase dependent manner. Thus, we conclude that Pfh1 is an accessory DNA helicase that interacts with the replisome and promotes replication and suppresses DNA damage at hard-to-replicate sites. These data provide insight into mechanisms by which this evolutionarily conserved helicase helps preserve genome integrity.

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Guise, Amanda J. (author)
Pourbozorgi-Langroudi, ParhamUmeå universitet,Institutionen för medicinsk kemi och biofysik(Swepub:umu)papo0009 (author)
Cristea, Ileana M. (author)
Zakian, Virginia A. (author)
Capra, John A. (author)
Sabouri, NasimUmeå universitet,Institutionen för medicinsk kemi och biofysik(Swepub:umu)namsai01 (author)
Umeå universitetInstitutionen för medicinsk kemi och biofysik (creator_code:org_t)

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In:PLOS Genetics: Copernicus GmbH12:91553-73901553-7404

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Other Basic Medi ...

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By the university: Umeå University

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