Garige Mamatha, Sharma Sudha
Department of Biochemistry and Molecular Biology, College of Medicine, Howard University, NW, Washington, DC, USA.
Department of Biochemistry and Molecular Biology, College of Medicine, Howard University, NW, Washington, DC, USA
Int J Toxicol. 2014 Sep-Oct;33(5):373-81. doi: 10.1177/1091581814547422. Epub 2014 Sep 15.
The 5 known RecQ helicases in humans (RECQ1, BLM, WRN, RECQL4, and RECQ5) have demonstrated roles in diverse genome maintenance mechanisms but their functions in safeguarding the genome from environmental toxicants are poorly understood. Here, we have evaluated a potential role of WRN (mutated in Werner syndrome) and RECQ1 (the most abundant homolog of WRN) in hydroquinone (HQ)- and benzo[a]pyrene (BaP)-induced genotoxicity. Silencing of WRN or RECQ1 expression in HeLa cells increased their sensitivity to HQ and BaP but elicited distinct DNA damage response. The RECQ1-depleted cells exhibited increased replication protein A phosphorylation, Chk1 activation, and DNA double-strand breaks (DSBs) as compared to control or WRN-depleted cells following exposure to BaP treatment. The BaP-induced DSBs in RECQ1-depleted cells were dependent on DNA-dependent protein kinase activity. Notably, loss of WRN in RECQ1-depleted cells ameliorated BaP toxicity. Collectively, our results provide first indication of nonredundant participation of WRN and RECQ1 in protection from the potentially carcinogenic effects of BaP and HQ.
人类已知的5种RecQ解旋酶（RECQ1、BLM、WRN、RECQ4和RECQ5）已在多种基因组维持机制中发挥作用，但它们在保护基因组免受环境毒物影响方面的功能却知之甚少。在此，我们评估了WRN（在沃纳综合征中发生突变）和RECQ1（WRN最丰富的同源物）在对苯二酚（HQ）和苯并[a]芘（BaP）诱导的遗传毒性中的潜在作用。在HeLa细胞中沉默WRN或RECQ1的表达会增加它们对HQ和BaP的敏感性，但引发不同的DNA损伤反应。与对照细胞或WRN缺失细胞相比，在暴露于BaP处理后，RECQ1缺失的细胞表现出复制蛋白A磷酸化增加、Chk1激活和DNA双链断裂（DSB）。RECQ1缺失细胞中BaP诱导的DSB依赖于DNA依赖性蛋白激酶活性。值得注意的是，在RECQ1缺失细胞中缺失WRN可改善BaP毒性。总的来说，我们的结果首次表明WRN和RECQ1在保护免受BaP和HQ的潜在致癌作用方面存在非冗余参与。
