METTL16 antagonizes MRE11-mediated DNA end resection and confers synthetic lethality to PARP inhibition in pancreatic ductal adenocarcinoma

被引：41

作者：

Zeng, Xiangyu ^{[1
,2
]}

Zhao, Fei ^{[2
]}

Cui, Gaofeng ^{[3
]}

Zhang, Yong ^{[4
]}

Deshpande, Rajashree A. ^{[5
]}

Chen, Yuping ^{[6
,7
]}

Deng, Min ^{[2
,8
,9
]}

Kloeber, Jake A. ^{[2
,10
]}

Shi, Yu ^{[2
,11
]}

Zhou, Qin ^{[2
]}

Zhang, Chao ^{[2
,12
]}

Hou, Jing ^{[2
,13
]}

Kim, Wootae ^{[14
]}

Tu, Xinyi ^{[2
]}

Yan, Yuanliang ^{[2
,15
]}

Xu, Zhijie ^{[2
,16
]}

Chen, Lifeng ^{[2
,17
]}

Gao, Huanyao ^{[18
]}

Guo, Guijie ^{[2
,19
]}

Liu, Jiaqi ^{[2
]}

Zhu, Qian ^{[2
,20
]}

Cao, Yueyu ^{[6
,7
]}

Huang, Jinzhou ^{[2
]}

Wu, Zheming ^{[2
]}

Zhu, Shouhai ^{[2
]}

Yin, Ping ^{[2
]}

Luo, Kuntian ^{[2
]}

Mer, Georges ^{[3
]}

Paull, Tanya T. ^{[5
]}

Yuan, Jian ^{[6
,7
]}

Tao, Kaixiong ^{[1
]}

Lou, Zhenkun ^{[2
]}

机构：

[1] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Gastrointestinal Surg, Wuhan, Peoples R China

[2] Mayo Clin, Dept Oncol, Rochester, MN 55902 USA

[3] Mayo Clin, Dept Biochem & Mol Biol, Rochester, MN USA

[4] Huazhong Univ Sci & Technol, Hubei Canc Hosp, Tongji Med Coll, Dept Radiat Oncol, Wuhan, Peoples R China

[5] Univ Texas Austin, Dept Mol Biosci, Austin, TX 78712 USA

[6] Tongji Univ, East Hosp, Res Ctr Translat Med, Key Lab Arrhythmias,Minist Educ China,Sch Med, Shanghai, Peoples R China

[7] Tongji Univ, Dept Biochem & Mol Biol, Sch Med, Shanghai, Peoples R China

[8] Chinese Acad Med Sci & Peking Union Med Coll, State Key Lab Mol Oncol, Natl Canc Ctr, Natl Clin Res Ctr Canc,Canc Hosp, Beijing, Peoples R China

[9] Chinese Acad Med Sci & Peking Union Med Coll, Dept Radiat Oncol, Natl Canc Ctr, Natl Clin Res Ctr Canc,Canc Hosp, Beijing, Peoples R China

[10] Mayo Clin, Mayo Clin Med Scientist Training Program, Rochester, MN USA

[11] Xi An Jiao Tong Univ, Dept Med Oncol, Affiliated Hosp 1, Xian, Peoples R China

[12] Beijing Inst Basic Med Sci, Beijing, Peoples R China

[13] Guizhou Prov Peoples Hosp, Dept Breast Surg, Guiyang, Peoples R China

[14] Soonchunhyang Univ, Soonchunhyang Inst Med Bio Sci SIMS, Cheonan Si, South Korea

[15] Cent South Univ, Xiangya Hosp, Dept Pharm, Changsha, Peoples R China

[16] Cent South Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr Disorders, Dept Pathol, Changsha, Peoples R China

[17] Hangzhou Med Coll, Ctr Reprod Med, Affiliated Peoples Hosp, Zhejiang Prov Peoples Hosp,Dept Gynecol, Hangzhou, Peoples R China

[18] Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN USA

[19] Fujian Agr & Forestry Univ, Coll Anim Sci, Key Lab Anim Pathogen Infect & Immunol Fujian Pro, Fuzhou, Peoples R China

[20] Shanghai Jiao Tong Univ, Ruijin Hosp, Dept Radiat Oncol, Sch Med, Shanghai, Peoples R China

来源：

NATURE CANCER | 2022年 / 3卷 / 09期

基金：

中国国家自然科学基金;

关键词：

HOMOLOGOUS RECOMBINATION; M(6)A METHYLTRANSFERASE; NAB-PACLITAXEL; MRE11; COMPLEX; REPAIR; GEMCITABINE; COMBINATION; VALIDATION; NUCLEASE; CELLS;

D O I：

10.1038/s43018-022-00429-3

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Characterization of genetic alterations will improve our understanding and therapies for this disease. Here, we report that PDAC with elevated expression of METTL16, one of the 'writers' of RNA N-6-methyladenosine modification, may benefit from poly-(ADP-ribose)-polymerase inhibitor (PARPi) treatment. Mechanistically, METTL16 interacts with MRE11 through RNA and this interaction inhibits MRE11's exonuclease activity in a methyltransferase-independent manner, thereby repressing DNA end resection. Upon DNA damage, ATM phosphorylates METTL16 resulting in a conformational change and autoinhibition of its RNA binding. This dissociates the METTL16-RNA-MRE11 complex and releases inhibition of MRE11. Concordantly, PDAC cells with high METTL16 expression show increased sensitivity to PARPi, especially when combined with gemcitabine. Thus, our findings reveal a role for METTL16 in homologous recombination repair and suggest that a combination of PARPi with gemcitabine could be an effective treatment strategy for PDAC with elevated METTL16 expression. Lou and colleagues describe the role of METTL16 in homologous recombination repair and demonstrate that PARP inhibition may be beneficial in the treatment of PDAC that is characterized by high METTL16.

引用

页码：1088 / +

页数：31