Laboratory of Molecular Gerontology, National Institute on Aging, 251 Bayview Blvd, Suite 100, Baltimore, MD 21224, USA.
Aging Cell. 2012 Jun;11(3):456-66. doi: 10.1111/j.1474-9726.2012.00803.x. Epub 2012 Mar 2.
RECQL4 is associated with Rothmund-Thomson Syndrome (RTS), a rare autosomal recessive disorder characterized by premature aging, genomic instability, and cancer predisposition. RECQL4 is a member of the RecQ helicase family, and has many similarities to WRN protein, which is also implicated in premature aging. There is no information about whether any of the RecQ helicases play roles in mitochondrial biogenesis, which is strongly implicated in the aging process. Here, we used microscopy to visualize RECQL4 in mitochondria. Fractionation of human and mouse cells also showed that RECQL4 was present in mitochondria. Q-PCR amplification of mitochondrial DNA demonstrated that mtDNA damage accumulated in RECQL4-deficient cells. Microarray analysis suggested that mitochondrial bioenergetic pathways might be affected in RTS. Measurements of mitochondrial bioenergetics showed a reduction in the mitochondrial reserve capacity after lentiviral knockdown of RECQL4 in two different primary cell lines. Additionally, biochemical assays with RECQL4, mitochondrial transcription factor A, and mitochondrial DNA polymerase γ showed that the polymerase inhibited RECQL4's helicase activity. RECQL4 is the first 3'-5' RecQ helicase to be found in both human and mouse mitochondria, and the loss of RECQL4 alters mitochondrial integrity.
RECQL4 与 Rothmund-Thomson 综合征（RTS）有关，RTS 是一种罕见的常染色体隐性遗传病，其特征为早衰、基因组不稳定和易患癌症。RECQL4 是 RecQ 解旋酶家族的成员，与 WRN 蛋白有许多相似之处，WRN 蛋白也与早衰有关。目前尚不清楚任何 RecQ 解旋酶是否在强烈暗示衰老过程的线粒体生物发生中发挥作用。在这里，我们使用显微镜观察线粒体中的 RECQL4。人源和鼠源细胞的分级分离也表明 RECQL4 存在于线粒体中。线粒体 DNA 的 Q-PCR 扩增表明，mtDNA 损伤在 RECQL4 缺陷细胞中积累。微阵列分析表明，RTS 中可能会影响线粒体生物能量途径。在两种不同的原代细胞系中，通过慢病毒敲低 RECQL4 后进行线粒体生物能量学测量，结果显示线粒体储备能力降低。此外，用 RECQL4、线粒体转录因子 A 和线粒体 DNA 聚合酶 γ 进行的生化分析表明，聚合酶抑制了 RECQL4 的解旋酶活性。RECQL4 是第一个在人和鼠源线粒体中都被发现的 3'-5' RecQ 解旋酶，并且 RECQL4 的缺失会改变线粒体的完整性。
