Co-occurrence of BAP1 and SF3B1 mutations in uveal melanoma induces cellular senescence.
Co-occurrence of BAP1 and SF3B1 mutations in uveal melanoma induces cellular senescence.
复制标题
DOI：
10.1002/1878-0261.13128
复制
发表时间：
2022-03
影响因子：
6.6
通讯作者：
Guan KL
中科院分区：
文献类型：
--
作者：
Yu L;Zhou D;Zhang G;Ren Z;Luo X;Liu P;Plouffe SW;Meng Z;Moroishi T;Li Y;Zhang Y;Brown JH;Liu S;Guan KL
葡萄膜黑色素瘤(UM)是成人最常见的眼内肿瘤。BRCA1相关蛋白1(BAP1)和剪接因子3B亚单位1(SF3B1)的反复突变在UM中显示出相互排斥的模式，但其潜在机制尚不清楚。我们发现BAP1缺乏和SF3B1热点突变共同导致人UM细胞衰老和生长停滞。虽然P53蛋白的表达被诱导，但TP53(编码P53)的缺失仅适度地挽救了观察到的衰老表型。BAP1缺失或SF3B1突变的UM细胞与其同源亲本细胞相比对化疗药物更敏感。转录组分析表明，当BAP1缺失和SF3B1突变同时发生时，DNA修复基因表达下调，从而导致DNA损伤反应减弱，诱导衰老。这两个突变的共存减少了斑马鱼异种移植模型中UM细胞的侵袭，并抑制了裸鼠黑色素瘤异种移植瘤的生长。我们的发现为人类UM中BAP1和SF3B1突变的互斥性提供了一个机制解释。BRCA-1相关蛋白1(BAP1)缺乏和剪接因子3B亚单位1(SF3B1)突变(R625H)共同存在的DNA修复基因的转录抑制会削弱细胞缓冲内源性DNA损伤的能力，从而导致DNA损伤和衰老。我们的发现为葡萄膜黑色素瘤中观察到的BAP1和SF3B1突变的互斥性提供了一个功能解释。
Uveal melanoma (UM) is the most common intraocular tumor in adults. Recurrent mutations in BRCA1‐associated protein 1 (BAP1) and splicing factor 3B subunit 1 (SF3B1) display a mutually exclusive pattern in UM, but the underlying mechanism is unknown. We show that combined BAP1 deficiency and SF3B1 hotspot mutation lead to senescence and growth arrest in human UM cells. Although p53 protein expression is induced, deletion of TP53 (encoding p53) only modestly rescues the observed senescent phenotype. UM cells with BAP1 loss or SF3B1 mutation are more sensitive to chemotherapeutic drugs compared with their isogenic parental cells. Transcriptome analysis shows that DNA‐repair genes are downregulated upon co‐occurrence of BAP1 deletion and SF3B1 mutation, thus leading to impaired DNA damage response and the induction of senescence. The co‐occurrence of these two mutations reduces invasion of UM cells in zebrafish xenograft models and suppresses growth of melanoma xenografts in nude mice. Our findings provide a mechanistic explanation for the mutual exclusivity of BAP1 and SF3B1 mutations in human UM. The transcriptional suppression of DNA‐repair genes derived from co‐occurrence of BRCA‐1‐associated protein 1 (BAP1) deficiency and splicing factor 3B subunit 1 (SF3B1) mutation (R625H) impairs cells’ capacity to buffer endogenous DNA damage and consequently leads to DNA damage and senescence. Our findings provide a functional explanation for the observed mutual exclusivity of BAP1 and SF3B1 mutations in uveal melanoma.
登录
查看更多内容
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
28.2
作者：
Carbone M;Harbour JW;Brugarolas J;Bononi A;Pagano I;Dey A;Krausz T;Pass HI;Yang H;Gaudino G
通讯作者：
Gaudino G
DOI：
10.1126/science.1194472
发表时间：
2010-12-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Harbour JW;Onken MD;Roberson ED;Duan S;Cao L;Worley LA;Council ML;Matatall KA;Helms C;Bowcock AM
通讯作者：
Bowcock AM
影响因子：
30.8
作者：
Harbour, J. William;Roberson, Elisha D. O.;Anbunathan, Hima;Onken, Michael D.;Worley, Lori A.;Bowcock, Anne M.
通讯作者：
Bowcock, Anne M.
DOI：
10.1007/978-1-62703-727-3_22
发表时间：
2014
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Harbour, J William
通讯作者：
Harbour, J William