53BP1 cooperation with the REV7-shieldin complex underpins DNA structure-specific NHEJ.
53BP1 cooperation with the REV7-shieldin complex underpins DNA structure-specific NHEJ.
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DOI：
10.1038/s41586-018-0362-1
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发表时间：
2018-08
期刊：
影响因子：
64.8
通讯作者：
Chapman JR
中科院分区：
文献类型：
--
作者：
Ghezraoui H;Oliveira C;Becker JR;Bilham K;Moralli D;Anzilotti C;Fischer R;Deobagkar-Lele M;Sanchiz-Calvo M;Fueyo-Marcos E;Bonham S;Kessler BM;Rottenberg S;Cornall RJ;Green CM;Chapman JR
53BP1调控经典的非同源末端连接(NHEJ)DNA双链断裂(DSB)修复途径的一个专门的、上下文特定的分支。53BP1-/-小鼠由于免疫球蛋白(Ig)类开关重组(CSR)的完全丧失和长程V(D)J重组保真度的降低而导致免疫缺陷。此外，53BP1依赖的通路还与功能失调的端粒的病理连接事件有关，其在BRCA1缺陷的细胞和肿瘤模型中的不受限制的活性导致基因组不稳定和肿瘤发生。与53BP1缺失的细胞不同，缺乏核心NHEJ蛋白的细胞对辐射非常敏感，这表明53BP1及其辅助因子作用于特定的DNA底物。在这里，我们证明了53BP1与其下游效应蛋白Rev7在CSR过程中协同促进NHEJ，而Rev7不是53BP1依赖的V(D)J重组所必需的。我们发现Shieldin是一个由Rev7、c20orf196(SHLD1)、FAM35A(SHLD2)和FLJ26957(SHLD3)组成的四亚基推测的单链DNA结合复合体，是解释这种特异性的因素。Shieldin在CSR过程中对Rev7依赖的DNA末端保护和NHEJ是必不可少的，并支持BRCA1缺陷细胞中的毒性NHEJ，但对于Rev7依赖的链间交链(ICL)修复是必不可少的。因此，53BP1途径在染色质和单链DNA(SsDNA)之间包含不同的DSB修复活性，这解释了53BP1和Rev7缺陷小鼠之间的免疫学差异和该途径的上下文特异性。
53BP1 governs a specialised, context-specific branch of the classical non-homologous end joining (NHEJ) DNA double-strand break (DSB) repair pathway. 53bp1-/- mice are immunodeficient owing to a complete loss of immunoglobulin (Ig) class-switch recombination (CSR), and reduced long-range V(D)J recombination fidelity. The 53BP1-dependent pathway is additionally responsible for pathological joining events at dysfunctional telomeres, and its unrestricted activity in BRCA1-deficient cellular and tumour models causes genomic instability and oncogenesis. Cells lacking core NHEJ proteins are profoundly radiosensitive, unlike 53BP1-deficient cells, suggesting that 53BP1 and its co-factors act on specific DNA substrates. Here, we show that 53BP1 cooperates with its downstream effector protein REV7 to promote NHEJ during CSR, yet REV7 is not required for 53BP1-dependent V(D)J recombination. We identify Shieldin, a four subunit putative single-stranded DNA-binding complex comprising REV7, c20orf196 (SHLD1), FAM35A (SHLD2), and FLJ26957 (SHLD3) as the factor that explains this specificity. Shieldin is essential for REV7-dependent DNA end-protection and NHEJ during CSR, and supports toxic NHEJ in BRCA1-deficient cells, yet is dispensable for REV7-dependent interstrand cross-link (ICL) repair. The 53BP1 pathway therefore comprises distinct DSB repair activities within chromatin and single-stranded DNA (ssDNA) compartments, which explains both the immunological differences between 53bp1- and Rev7- deficient mice and the pathway’s context specificity.
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影响因子：
64.8
作者：
Skarnes WC;Rosen B;West AP;Koutsourakis M;Bushell W;Iyer V;Mujica AO;Thomas M;Harrow J;Cox T;Jackson D;Severin J;Biggs P;Fu J;Nefedov M;de Jong PJ;Stewart AF;Bradley A
通讯作者：
Bradley A
影响因子：
30.5
作者：
Manis, JP;Morales, JC;Carpenter, PB
通讯作者：
Carpenter, PB
影响因子：
14.8
作者：
Kelley LA;Mezulis S;Yates CM;Wass MN;Sternberg MJ
通讯作者：
Sternberg MJ
DOI：
10.4049/jimmunol.1401849
发表时间：
2014-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Stavnezer J;Schrader CE
通讯作者：
Schrader CE
影响因子：
2.5
作者：
Adams, IR;McLaren, A
通讯作者：
McLaren, A