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DPPA5A suppresses the mutagenic TLS and MMEJ pathways by modulating the cryptic splicing of Rev1 and Polq in mouse embryonic stem cells

文献类型：期刊论文

作者Jiang, Fangjie5,6,7; Wang, Lin4,7; Dong, Yuping4,6,7; Nie, Wenhui7; Zhou, Hu2,3; Gao, Jing2,3; Zheng, Ping1,4,7
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
出版日期2023-07-25
卷号120期号:30页码:11
关键词embryonic stem cells cryptic exon DPPA5A Rev1 Polq
ISSN号0027-8424
DOI10.1073/pnas.2305187120
通讯作者Zheng, Ping(zhengp@mail.kiz.ac.cn)
英文摘要Genetic alterations are often acquired during prolonged propagation of pluripotent stem cells (PSCs). This ruins the stem cell quality and hampers their full applications. Understanding how PSCs maintain genomic integrity would provide the clues to over-come the hurdle. It has been known that embryonic stem cells (ESCs) utilize high-fidelity pathways to ensure genomic stability, but the underlying mechanisms remain largely elusive. Here, we show that many DNA damage response and repair genes display differ-ential alternative splicing in mouse ESCs compared to differentiated cells. Particularly, Rev1 and Polq, two key genes for mutagenic translesion DNA synthesis (TLS) and microhomology-mediated end joining (MMEJ) repair pathways, respectively, display a significantly higher rate of cryptic exon (CE) inclusion in ESCs. The frequent CE inclu-sion disrupts the normal protein expressions of REV1 and POLO, thereby suppressing the mutagenic TLS and MMEJ. Further, we identify an ESC-specific RNA binding protein DPPA5A which stimulates the CE inclusion in Rev1 and Polq. Depletion of DPPA5A in mouse ESCs decreased the CE inclusion of Rev1 and Polq, induced the protein expression, and stimulated the TLS and MMEJ activity. Enforced expression of DPPA5A in NIH3T3 cells displayed reverse effects. Mechanistically, we found that DPPA5A directly regulated CE splicing of Rev1. DPPA5A associates with U2 small nuclear ribonucleoprotein of the spliceosome and binds to the GA -rich motif in the CE of Rev1 to promote CE inclusion. Thus, our study uncovers a mechanism to suppress mutagenic TLS and MMEJ pathways in ESCs.
WOS关键词DNA-DAMAGE RESPONSE ; RNA-BINDING PROTEIN ; REPAIR ; DIFFERENTIATION ; TRANSCRIPTOME ; PLURIPOTENCY ; EXPRESSION ; REGULATOR ; STABILITY ; VARIANTS
资助项目National Key Research & Developmental Program of China[2021YFA1102000] ; National Natural Science Foundation of China[31930027] ; Yunnan Fundamental Research Projects[202301AS070062]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001083464000008
出版者NATL ACAD SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/307566]  
专题中国科学院上海药物研究所
通讯作者Zheng, Ping
作者单位1.Chinese Acad Sci, Chinese Univ Hong Kong & Kunming Inst Zool Joint, Kunming Inst Zool, Kunming 650223, Yunnan, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Analyt Chem, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Kunming Inst Zool, Key Lab Anim Models & Human Dis Mech Yunnan Prov, Kunming 650223, Yunnan, Peoples R China
5.Kunming Med Univ, Dept Reprod Med, Affiliated Hosp 2, Kunming 650101, Peoples R China
6.Univ Chinese Acad Sci, Beijing 101408, Peoples R China
7.Chinese Acad Sci, Kunming Inst Zool, State Key Lab Genet Resources & Evolut, Kunming 650223, Yunnan, Peoples R China
推荐引用方式
GB/T 7714		 Jiang, Fangjie,Wang, Lin,Dong, Yuping,et al. DPPA5A suppresses the mutagenic TLS and MMEJ pathways by modulating the cryptic splicing of Rev1 and Polq in mouse embryonic stem cells[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2023,120(30):11.
APA Jiang, Fangjie.,Wang, Lin.,Dong, Yuping.,Nie, Wenhui.,Zhou, Hu.,...&Zheng, Ping.(2023).DPPA5A suppresses the mutagenic TLS and MMEJ pathways by modulating the cryptic splicing of Rev1 and Polq in mouse embryonic stem cells.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,120(30),11.
MLA Jiang, Fangjie,et al."DPPA5A suppresses the mutagenic TLS and MMEJ pathways by modulating the cryptic splicing of Rev1 and Polq in mouse embryonic stem cells".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 120.30(2023):11.

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来源：上海药物研究所

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