title: RAD52 Facilitates Mitotic DNA Synthesis Following Replication Stress.
abstract: Homologous recombination (HR) is necessary to counteract DNA replication stress. Common fragile site (CFS) loci are particularly sensitive to replication stress and undergo pathological rearrangements in tumors. At these loci, replication stress frequently activates DNA repair synthesis in mitosis. This mitotic DNA synthesis, termed MiDAS, requires the MUS81-EME1 endonuclease and a non-catalytic subunit of the Pol-delta complex, POLD3. Here, we examine the contribution of HR factors in promoting MiDAS in human cells. We report that RAD51 and BRCA2 are dispensable for MiDAS but are required to counteract replication stress at CFS loci during S-phase. In contrast, MiDAS is RAD52 dependent, and RAD52 is required for the timely recruitment of MUS81 and POLD3 to CFSs in early mitosis. Our results provide further mechanistic insight into MiDAS and define a specific function for human RAD52. Furthermore, selective inhibition of MiDAS may comprise a potential therapeutic strategy to sensitize cancer cells undergoing replicative stress.
authors.affiliation: Center for Chromosome Stability and Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Rahul
authors.initials: R
authors.lastname: Bhowmick
authors.affiliation: Center for Chromosome Stability and Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Sheroy
authors.initials: S
authors.lastname: Minocherhomji
authors.affiliation: Center for Chromosome Stability and Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen N, Denmark. Electronic address: iandh@sund.ku.dk.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Hickson
mesh_terms: D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D043283:Chromosome Fragile Sites; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D004258:DNA Polymerase III / Q000235:genetics* / Q000378:metabolism; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D051721:Rad52 DNA Repair and Recombination Protein / Q000235:genetics* / Q000378:metabolism; D059767:Recombinational DNA Repair; D013312:Stress, Physiological
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D004268:DNA-Binding Proteins; C497194:RAD52 protein, human; D051721:Rad52 DNA Repair and Recombination Protein; D004247:DNA; C435720:POLD3 protein, human; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D004258:DNA Polymerase III; C507947:Eme1 protein, human; D004706:Endodeoxyribonucleases; D004720:Endonucleases; C498772:MUS81 protein, human
keywords: break-induced replication; conservative DNA synthesis; homologous recombination; mitosis; replication stress