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RUVBL1/RUVBL2 ATPase Activity Drives PAQosome Maturation, DNA Replication and Radioresistance in Lung Cancer.
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2019-12-20 , DOI: 10.1016/j.chembiol.2019.12.005 Paul Yenerall 1 , Amit K Das 2 , Shan Wang 3 , Rahul K Kollipara 4 , Long Shan Li 2 , Pamela Villalobos 5 , Josiah Flaming 2 , Yu-Fen Lin 6 , Kenneth Huffman 2 , Brenda C Timmons 2 , Collin Gilbreath 7 , Rajni Sonavane 7 , Lisa N Kinch 8 , Jaime Rodriguez-Canales 5 , Cesar Moran 9 , Carmen Behrens 10 , Makoto Hirasawa 11 , Takehiko Takata 12 , Ryo Murakami 13 , Koichi Iwanaga 12 , Benjamin P C Chen 6 , Nick V Grishin 8 , Ganesh V Raj 14 , Ignacio I Wistuba 15 , John D Minna 16 , Ralf Kittler 17
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2019-12-20 , DOI: 10.1016/j.chembiol.2019.12.005 Paul Yenerall 1 , Amit K Das 2 , Shan Wang 3 , Rahul K Kollipara 4 , Long Shan Li 2 , Pamela Villalobos 5 , Josiah Flaming 2 , Yu-Fen Lin 6 , Kenneth Huffman 2 , Brenda C Timmons 2 , Collin Gilbreath 7 , Rajni Sonavane 7 , Lisa N Kinch 8 , Jaime Rodriguez-Canales 5 , Cesar Moran 9 , Carmen Behrens 10 , Makoto Hirasawa 11 , Takehiko Takata 12 , Ryo Murakami 13 , Koichi Iwanaga 12 , Benjamin P C Chen 6 , Nick V Grishin 8 , Ganesh V Raj 14 , Ignacio I Wistuba 15 , John D Minna 16 , Ralf Kittler 17
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RUVBL1 and RUVBL2 (collectively RUVBL1/2) are essential AAA+ ATPases that function as co-chaperones and have been implicated in cancer. Here we investigated the molecular and phenotypic role of RUVBL1/2 ATPase activity in non-small cell lung cancer (NSCLC). We find that RUVBL1/2 are overexpressed in NSCLC patient tumors, with high expression associated with poor survival. Utilizing a specific inhibitor of RUVBL1/2 ATPase activity, we show that RUVBL1/2 ATPase activity is necessary for the maturation or dissociation of the PAQosome, a large RUVBL1/2-dependent multiprotein complex. We also show that RUVBL1/2 have roles in DNA replication, as inhibition of its ATPase activity can cause S-phase arrest, which culminates in cancer cell death via replication catastrophe. While in vivo pharmacological inhibition of RUVBL1/2 results in modest antitumor activity, it synergizes with radiation in NSCLC, but not normal cells, an attractive property for future preclinical development.
中文翻译：
RUVBL1 / RUVBL2 ATPase活性驱动肺癌中PAQosome的成熟，DNA复制和抗辐射性。
RUVBL1和RUVBL2（统称为RUVBL1 / 2）是必需的AAA + ATP酶，可充当伴侣分子并与癌症有关。在这里，我们调查了RUVBL1 / 2 ATPase活性在非小细胞肺癌（NSCLC）中的分子和表型作用。我们发现RUVBL1 / 2在NSCLC患者肿瘤中过表达，且表达高与生存期差有关。利用RUVBL1 / 2 ATPase活性的特定抑制剂，我们表明RUVBL1 / 2 ATPase活性对于PAQosome（一种依赖于RUVBL1 / 2的大型多蛋白复合物）的成熟或解离是必需的。我们还表明，RUVBL1 / 2在DNA复制中具有作用，因为对其ATPase活性的抑制会导致S期停滞，最终导致复制灾难导致癌细胞死亡。
更新日期：2019-12-27
中文翻译：
RUVBL1 / RUVBL2 ATPase活性驱动肺癌中PAQosome的成熟，DNA复制和抗辐射性。
RUVBL1和RUVBL2（统称为RUVBL1 / 2）是必需的AAA + ATP酶，可充当伴侣分子并与癌症有关。在这里，我们调查了RUVBL1 / 2 ATPase活性在非小细胞肺癌（NSCLC）中的分子和表型作用。我们发现RUVBL1 / 2在NSCLC患者肿瘤中过表达，且表达高与生存期差有关。利用RUVBL1 / 2 ATPase活性的特定抑制剂，我们表明RUVBL1 / 2 ATPase活性对于PAQosome（一种依赖于RUVBL1 / 2的大型多蛋白复合物）的成熟或解离是必需的。我们还表明，RUVBL1 / 2在DNA复制中具有作用，因为对其ATPase活性的抑制会导致S期停滞，最终导致复制灾难导致癌细胞死亡。
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