title: PTEN regulates DNA replication progression and stalled fork recovery.
abstract: Faithful DNA replication is a cornerstone of genomic integrity. PTEN plays multiple roles in genome protection and tumour suppression. Here we report on the importance of PTEN in DNA replication. PTEN depletion leads to impairment of replication progression and stalled fork recovery, indicating an elevation of endogenous replication stress. Exogenous replication inhibition aggravates replication-originated DNA lesions without inducing S phase arrest in cells lacking PTEN, representing replication stress tolerance. iPOND analysis reveals the physical association of PTEN with DNA replication forks and PTEN-dependent recruitment of Rad51. PTEN deletion results in Rad51 dissociation from replication forks. Stalled replication forks in Pten-null cells can be reactivated by ectopic Rad51 or PTEN, the latter facilitating chromatin loading of Rad51. These data highlight the interplay of PTEN with Rad51 in promoting stalled fork restart. We propose that loss of PTEN may initiate a replication stress cascade that progressively deteriorates through the cell cycle.
authors.affiliation: Department of Radiation Oncology, Weill Medical College of Cornell University, New York 10065, USA.
authors.forename: Jinxue
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Radiation Oncology, Weill Medical College of Cornell University, New York 10065, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Kang
authors.affiliation: Department of Radiation Oncology, Weill Medical College of Cornell University, New York 10065, USA.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Department of Radiation Oncology, Weill Medical College of Cornell University, New York 10065, USA.
authors.forename: K S Clifford
authors.initials: KS
authors.lastname: Chao
authors.affiliation: Department of Radiation Oncology, Weill Medical College of Cornell University, New York 10065, USA.
authors.forename: Wen H
authors.initials: WH
authors.lastname: Shen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D004261:DNA Replication / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D051135:Rad51 Recombinase / Q000378:metabolism*; D059807:S Phase Cell Cycle Checkpoints / Q000235:genetics
chemical_list: D002843:Chromatin; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; C495154:Rad51 protein, mouse; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse