Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome Chaperone Activity of FANCD2.
Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome Chaperone Activity of FANCD2.
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DOI：
10.1016/j.molcel.2018.05.018
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发表时间：
2018-07-05
期刊：
影响因子：
16
通讯作者：
Stewart GS
中科院分区：
文献类型：
--
作者：
Higgs MR;Sato K;Reynolds JJ;Begum S;Bayley R;Goula A;Vernet A;Paquin KL;Skalnik DG;Kobayashi W;Takata M;Howlett NG;Kurumizaka H;Kimura H;Stewart GS
范可尼贫血和同源重组途径的组成部分在保护新复制的DNA免受不受控制的溶核降解，维护基因组稳定性方面起着至关重要的作用。在这里，我们报告组蛋白甲基化的赖氨酸甲基转移酶SETD1A是至关重要的保护停滞复制叉有害切除。SETD1A的缺失使细胞对复制应激敏感，并导致受损复制叉的不受控制的DNA2依赖性切除。SETD1A防止这些结构降解的能力是通过其在复制叉处催化组蛋白H3（H3K4）的Lys4上的甲基化的能力介导的，这增强了FANCD 2依赖性组蛋白伴侣活性。抑制H3K4甲基化或伴侣蛋白缺陷型FANCD2突变体的表达导致RAD 51核丝稳定性丧失和复制叉的严重溶核降解。我们的工作确定表观遗传修饰和组蛋白流动性的关键调控机制，在维持基因组的稳定性，抑制核酸酶不可挽回地破坏停滞的复制叉。通过SETD1A甲基化H3K4在复制应激期间维持基因组稳定性SETD1A和H3K4甲基化稳定RAD51核丝以保护新生DNA SETD1A依赖性H3K4甲基化增强FANCD 2依赖性组蛋白重塑组蛋白迁移率稳定RAD51核丝以抑制叉降解Higgs et al.通过增强FANCD 2依赖性核小体重塑，鉴定组蛋白H3K4甲基化对于在复制应激期间防止基因组不稳定性至关重要。FANCD2引起的SETD1A缺失或H3动员不足导致RAD 51核丝不稳定性和停滞复制叉的严重溶核降解。
Components of the Fanconi anemia and homologous recombination pathways play a vital role in protecting newly replicated DNA from uncontrolled nucleolytic degradation, safeguarding genome stability. Here we report that histone methylation by the lysine methyltransferase SETD1A is crucial for protecting stalled replication forks from deleterious resection. Depletion of SETD1A sensitizes cells to replication stress and leads to uncontrolled DNA2-dependent resection of damaged replication forks. The ability of SETD1A to prevent degradation of these structures is mediated by its ability to catalyze methylation on Lys4 of histone H3 (H3K4) at replication forks, which enhances FANCD2-dependent histone chaperone activity. Suppressing H3K4 methylation or expression of a chaperone-defective FANCD2 mutant leads to loss of RAD51 nucleofilament stability and severe nucleolytic degradation of replication forks. Our work identifies epigenetic modification and histone mobility as critical regulatory mechanisms in maintaining genome stability by restraining nucleases from irreparably damaging stalled replication forks. Methylation of H3K4 by SETD1A maintains genome stability during replication stress SETD1A and H3K4 methylation stabilize RAD51 nucleofilaments to protect nascent DNA SETD1A-dependent H3K4 methylation enhances FANCD2-dependent histone remodeling Histone mobility stabilizes RAD51 nucleofilaments to inhibit fork degradation Higgs et al. identify histone H3K4 methylation by SETD1A as essential to prevent genome instability during replication stress by enhancing FANCD2-dependent nucleosome remodeling. Loss of SETD1A or deficiencies in H3 mobilization by FANCD2 leads to RAD51 nucleofilament instability and severe nucleolytic degradation of stalled replication forks.
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影响因子：
16
作者：
Calo, Eliezer;Wysocka, Joanna
通讯作者：
Wysocka, Joanna
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16
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Nussenzweig A
影响因子：
4.8
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