title: Sensitivity of RECQL4-deficient fibroblasts from Rothmund-Thomson syndrome patients to genotoxic agents.
abstract: RECQ helicase protein-like 4 (RECQL4) is a member of the human RECQ family of DNA helicases. Two-thirds of patients with Rothmund-Thomson syndrome (RTS) carry biallelic inactivating mutations in the RECQL4 gene. RTS is an autosomal recessive disorder characterized by poikiloderma, sparse hair, small stature, skeletal abnormalities, cataracts, and an increased risk of cancer. Mutations in two other RECQ helicases, BLM and WRN, are responsible for the cancer predisposition conditions Bloom and Werner syndromes, respectively. Previous studies have shown that BLM and WRN-deficient cells demonstrate increased sensitivity to hydroxyurea (HU), camptothecin (CPT), and 4-nitroquinoline 1-oxide (4NQO). Little is known about the sensitivity of RECQL4-deficient cells to these and other genotoxic agents. The purpose of this study was to determine if RTS cells display any distinct cellular phenotypes in response to DNA damaging agents or replication blocks that could provide insight into the molecular function of the RECQL4 protein. Our results show that primary fibroblasts from RTS patients carrying two deleterious RECQL4 mutations, compared to wild type (WT) fibroblasts, have increased sensitivity to HU, CPT, and doxorubicin (DOX), modest sensitivity to other DNA damaging agents including ultraviolet (UV) irradiation, ionizing radiation (IR), and cisplatin (CDDP), and relative resistance to 4NQO. The RECQ family of DNA helicases has been implicated in the regulation of DNA replication, recombination, and repair. Because HU, CPT, and DOX exert their effects primarily during S phase, these results support a greater role for the RECQL4 protein in DNA replication as opposed to repair of exogenous damage.
authors.affiliation: Department of Pediatrics, Section of Hematology/Oncology, Texas Children's Cancer Center, Baylor College of Medicine, 6621 Fannin MC 3-3320, Houston, TX 77030, USA.
authors.forename: Weidong
authors.initials: W
authors.lastname: Jin
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Subhendu K
authors.initials: SK
authors.lastname: Otta
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Plon
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Wang
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity; D000970:Antineoplastic Agents / Q000633:toxicity; D002166:Camptothecin / Q000633:toxicity; D002945:Cisplatin / Q000633:toxicity; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics; D004317:Doxorubicin / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D004351:Drug Resistance / Q000235:genetics*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006918:Hydroxyurea / Q000633:toxicity; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D020641:Polymorphism, Single Nucleotide; D011839:Radiation, Ionizing; D053484:RecQ Helicases / Q000235:genetics* / Q000378:metabolism; D011038:Rothmund-Thomson Syndrome / Q000473:pathology*; D014466:Ultraviolet Rays
chemical_list: D000970:Antineoplastic Agents; D009153:Mutagens; D015112:4-Nitroquinoline-1-oxide; D004317:Doxorubicin; C506731:RECQL4 protein, human; D053484:RecQ Helicases; D002945:Cisplatin; D006918:Hydroxyurea; D002166:Camptothecin