title: hMSH5 Facilitates the Repair of Camptothecin-induced Double-strand Breaks through an Interaction with FANCJ.
abstract: Replication stress from stalled or collapsed replication forks is a major challenge to genomic integrity. The anticancer agent camptothecin (CPT) is a DNA topoisomerase I inhibitor that causes fork collapse and double-strand breaks amid DNA replication. Here we report that hMSH5 promotes cell survival in response to CPT-induced DNA damage. Cells deficient in hMSH5 show elevated CPT-induced γ-H2AX and RPA2 foci with concomitant reduction of Rad51 foci, indicative of impaired homologous recombination. In addition, CPT-treated hMSH5-deficient cells exhibit aberrant activation of Chk1 and Chk2 kinases and therefore abnormal cell cycle progression. Furthermore, the hMSH5-FANCJ chromatin recruitment underlies the effects of hMSH5 on homologous recombination and Chk1 activation. Intriguingly, FANCJ depletion desensitizes hMSH5-deficient cells to CPT-elicited cell killing. Collectively, our data point to the existence of a functional interplay between hMSH5 and FANCJ in double-strand break repair induced by replication stress.
authors.affiliation: From the School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Pullman, Washington 99164-7520.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: From the School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Pullman, Washington 99164-7520.
authors.forename: Xiling
authors.initials: X
authors.lastname: Wu
authors.affiliation: From the School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Pullman, Washington 99164-7520 cher@wsu.edu.
authors.forename: Chengtao
authors.initials: C
authors.lastname: Her
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D002166:Camptothecin / Q000633:toxicity; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics*; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics* / Q000378:metabolism; D059765:Homologous Recombination; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D011494:Protein Kinases / Q000378:metabolism; D051135:Rad51 Recombinase / Q000235:genetics* / Q000378:metabolism
chemical_list: C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D018797:Cell Cycle Proteins; D051856:Fanconi Anemia Complementation Group Proteins; C118481:MSH5 protein, human; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D002166:Camptothecin
keywords: DNA damage; DNA repair; DNA replication; DNA topoisomerase; DNA-binding protein