气候变化领域集成服务门户(CCPortal): Ku70 suppresses alternative end joining in G1-arrested progenitor B cells

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DOI	10.1073/pnas.2103630118
	Ku70 suppresses alternative end joining in G1-arrested progenitor B cells
	Liang Z.; Kumar V.; Le Bouteiller M.; Zurita J.; Kenrick J.; Lin S.G.; Lou J.; Hu J.; Ye A.Y.; Boboila C.; Alt F.W.; Frock R.L.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:21
英文摘要	Classical nonhomologous end joining (C-NHEJ) repairs DNA double-strand breaks (DSBs) throughout interphase but predominates in G1 phase when homologous recombination is unavailable. Complexes containing the Ku70/80 (“Ku”) and XRCC4/ligase IV (Lig4) core C-NHEJ factors are required, respectively, for sensing and joining DSBs. While XRCC4/Lig4 are absolutely required for joining RAG1/ 2 endonuclease (“RAG”)-initiated DSBs during V(D)J recombination in G1-phase progenitor lymphocytes, cycling cells deficient for XRCC4/Lig4 also can join chromosomal DSBs by alternative end-joining (A-EJ) pathways. Restriction of V(D)J recombination by XRCC4/Lig4-mediated joining has been attributed to RAG shepherding V(D)J DSBs exclusively into the C-NHEJ pathway. Here, we report that A-EJ of DSB ends generated by RAG1/2, Cas9:gRNA, and Zinc finger endonucleases in Lig4-deficient G1-arrested progenitor B cell lines is suppressed by Ku. Thus, while diverse DSBs remain largely as free broken ends in Lig4-deficient G1-arrested progenitor B cells, deletion of Ku70 increases DSB rejoining and translocation levels to those observed in Ku70-deficient counterparts. Correspondingly, while RAG-initiated V(D)J DSB joining is abrogated in Lig4-deficient G1-arrested progenitor B cell lines, joining of RAG-generated DSBs in Ku70-deficient and Ku70/Lig4 double-deficient lines occurs through a translocation-like A-EJ mechanism. Thus, in G1-arrested, Lig4-deficient progenitor B cells are functionally end-joining suppressed due to Ku-dependent blockage of A-EJ, potentially in association with G1-phase down-regulation of Lig1. Finally, we suggest that differential impacts of Ku deficiency versus Lig4 deficiency on V(D)J recombination, neuronal apoptosis, and embryonic development results from Ku-mediated inhibition of A-EJ in the G1 cell cycle phase in Lig4-deficient developing lymphocyte and neuronal cells. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Cas9; DSB repair; End joining; G1 phase; V(D)J recombination
语种	英语
scopus关键词	caspase 9; endonuclease; Ku antigen; RAG1 protein; zinc finger protein; ATP dependent DNA ligase; DNA binding protein; homeodomain protein; Ku antigen; LIG4 protein, human; nuclear protein; RAG-1 protein; RAG2 protein, human; XRCC4 protein, human; XRCC5 protein, human; Xrcc6 protein, human; animal cell; animal experiment; Article; cell maturation; controlled study; double stranded DNA break; down regulation; embryo development; G1 phase cell cycle checkpoint; gene amplification; gene deletion; gene mapping; gene repression; gene translocation; genetic database; genome-wide association study; high throughput sequencing; mouse; nerve cell; neuroapoptosis; nonhuman; pre B lymphocyte; signal transduction; animal; cell cycle G1 phase; cytology; DNA end joining repair; double stranded DNA break; gene expression regulation; genetics; human; metabolism; pre B lymphocyte; transgenic mouse; VDJ recombination; Animals; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Ligase ATP; DNA-Binding Proteins; G1 Phase; Gene Expression Regulation; Homeodomain Proteins; Humans; Ku Autoantigen; Mice; Mice, Transgenic; Nuclear Proteins; Precursor Cells, B-Lymphoid; V(D)J Recombination
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251177
作者单位	HHMI, Boston Children’s Hospital, Boston, MA 02115, United States; Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, United States; Department of Genetics, Harvard Medical School, Boston, MA 02115, United States; Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, United States
推荐引用方式 GB/T 7714	Liang Z.,Kumar V.,Le Bouteiller M.,et al. Ku70 suppresses alternative end joining in G1-arrested progenitor B cells[J],2021,118(21).
APA	Liang Z..,Kumar V..,Le Bouteiller M..,Zurita J..,Kenrick J..,...&Frock R.L..(2021).Ku70 suppresses alternative end joining in G1-arrested progenitor B cells.Proceedings of the National Academy of Sciences of the United States of America,118(21).
MLA	Liang Z.,et al."Ku70 suppresses alternative end joining in G1-arrested progenitor B cells".Proceedings of the National Academy of Sciences of the United States of America 118.21(2021).