Jin Weidong, Liu Hao, Zhang Yiqun, Otta Subhendu K, Plon Sharon E, Wang Lisa L
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.
Hum Genet. 2008 Jul;123(6):643-53. doi: 10.1007/s00439-008-0518-4. Epub 2008 May 27.
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.
RECQ解旋酶样蛋白4（RECQL4）是人类RECQ DNA解旋酶家族的成员。三分之二的罗特蒙德-汤姆森综合征（RTS）患者在RECQ4基因中携带双等位基因失活突变。RTS是一种常染色体隐性疾病，其特征为皮肤异色症、头发稀疏、身材矮小、骨骼异常、白内障以及患癌风险增加。另外两种RECQ解旋酶BLM和WRN的突变分别导致了布卢姆综合征和沃纳综合征这两种癌症易感疾病。先前的研究表明，缺乏BLM和WRN的细胞对羟基脲（HU）、喜树碱（CPT）和4-硝基喹啉1-氧化物（4NQO）表现出更高的敏感性。关于缺乏RECQL4的细胞对这些及其他基因毒性剂的敏感性知之甚少。本研究的目的是确定RTS细胞在应对DNA损伤剂或复制阻滞时是否表现出任何独特的细胞表型，从而有助于深入了解RECQL4蛋白的分子功能。我们的结果表明，与野生型（WT）成纤维细胞相比，携带两个有害RECQ4突变的RTS患者的原代成纤维细胞对HU、CPT和阿霉素（DOX）的敏感性增加，对包括紫外线（UV）照射、电离辐射（IR）和顺铂（CDDP）在内的其他DNA损伤剂有适度敏感性，而对4NQO具有相对抗性。DNA解旋酶的RECQ家族与DNA复制、重组和修复的调节有关。由于HU、CPT和DOX主要在S期发挥作用，这些结果支持RECQL4蛋白在DNA复制中而非在外源损伤修复中发挥更大作用。
