title: RECQL5 and BLM exhibit divergent functions in cells defective for the Fanconi anemia pathway.
abstract: Fanconi anemia (FA) patients exhibit bone marrow failure, developmental defects and cancer. The FA pathway maintains chromosomal stability in concert with replication fork maintenance and DNA double strand break (DSB) repair pathways including RAD51-mediated homologous recombination (HR). RAD51 is a recombinase that maintains replication forks and repairs DSBs, but also rearranges chromosomes. Two RecQ helicases, RECQL5 and Bloom syndrome mutated (BLM) suppress HR through nonredundant mechanisms. Here we test the impact deletion of RECQL5 and BLM has on mouse embryonic stem (ES) cells deleted for FANCB, a member of the FA core complex. We show that RECQL5, but not BLM, conferred resistance to mitomycin C (MMC, an interstrand crosslinker) and camptothecin (CPT, a type 1 topoisomerase inhibitor) in FANCB-defective cells. RECQL5 suppressed, while BLM caused, breaks and radials in FANCB-deleted cells exposed to CPT or MMC, respectively. RECQL5 protected the nascent replication strand from MRE11-mediated degradation and restarted stressed replication forks in a manner additive to FANCB. By contrast BLM restarted, but did not protect, replication forks in a manner epistatic to FANCB. RECQL5 also lowered RAD51 levels in FANCB-deleted cells at stressed replication sites implicating a rearrangement avoidance mechanism. Thus, RECQL5 and BLM impact FANCB-defective cells differently in response to replication stress with relevance to chemotherapeutic regimes.
authors.affiliation: Department of Molecular Medicine and Institute of Biotechnology, The Barshop Center of Aging, University of Texas Health Science Center, San Antonio, TX 78245, USA.
authors.forename: Tae Moon
authors.initials: TM
authors.lastname: Kim
authors.affiliation: Department of Molecular Medicine and Institute of Biotechnology, The Barshop Center of Aging, University of Texas Health Science Center, San Antonio, TX 78245, USA.
authors.forename: Mi Young
authors.initials: MY
authors.lastname: Son
authors.affiliation: Department of Molecular Medicine and Institute of Biotechnology, The Barshop Center of Aging, University of Texas Health Science Center, San Antonio, TX 78245, USA.
authors.forename: Sherry
authors.initials: S
authors.lastname: Dodds
authors.affiliation: Department of Molecular Medicine and Institute of Biotechnology, The Barshop Center of Aging, University of Texas Health Science Center, San Antonio, TX 78245, USA.
authors.forename: Lingchuan
authors.initials: L
authors.lastname: Hu
authors.affiliation: Department of Genetics, Case Western Reserve University, BRB-720, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: Guangbin
authors.initials: G
authors.lastname: Luo
authors.affiliation: Department of Molecular Medicine and Institute of Biotechnology, The Barshop Center of Aging, University of Texas Health Science Center, San Antonio, TX 78245, USA hastye@uthscsa.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Hasty
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004261:DNA Replication; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D051379:Mice; D053484:RecQ Helicases / Q000235:genetics / Q000502:physiology*
chemical_list: D051856:Fanconi Anemia Complementation Group Proteins; C097151:Bloom syndrome protein; D053484:RecQ Helicases; C501069:Recql5 protein, mouse