The SAGA Deubiquitination Module Promotes DNA Repair and Class Switch Recombination through ATM and DNAPK-Mediated γH2AX Formation.
The SAGA Deubiquitination Module Promotes DNA Repair and Class Switch Recombination through ATM and DNAPK-Mediated γH2AX Formation.
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DOI：
10.1016/j.celrep.2016.04.041
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发表时间：
2016-05-17
期刊：
影响因子：
8.8
通讯作者：
Martin A
中科院分区：
文献类型：
--
作者：
Ramachandran S;Haddad D;Li C;Le MX;Ling AK;So CC;Nepal RM;Gommerman JL;Yu K;Ketela T;Moffat J;Martin A
类开关重组(CSR)需要激活诱导的脱氨酶(AID)来激发免疫球蛋白基因座的双链DNA断裂。DNA断裂通过诱导组蛋白H_2AX的磷酸化和非同源末端连接(NHEJ)修复来激活DNA损伤反应(DDR)。我们进行了全基因组筛查，以确定CSR因子。我们发现，Usp22、Eny2和Atxn7是SPT-Ada-Gcn5-乙酰基转移酶(SAGA)去泛素化模块的成员，是DNA损伤后H2BK120ub去泛素化所必需的，在CSR中起关键作用，并且在AID的下游发挥作用。SAGA脱泛素酶活性是辐射诱导γH_2AX形成所必需的，不去除H_2BK120ub会抑制ATM和DNAPK诱导的γH_2AX形成。与这种效应一致的是，这些蛋白质被发现在各种双链DNA修复途径的上游发挥作用。这份报告表明，组蛋白H2B的去泛素化影响DDR的早期阶段，并且是CSR的DNA修复阶段所必需的。
Class switch recombination (CSR) requires activation-induced deaminase (AID) to instigate double-stranded DNA breaks at the immunoglobulin locus. DNA breaks activate the DNA damage response (DDR) by inducing phosphorylation of histone H2AX followed by non-homologous end joining (NHEJ) repair. We carried out a genome-wide screen to identify CSR factors. We found that Usp22, Eny2, and Atxn7, members of the Spt-Ada-Gcn5-acetyltransferase (SAGA) deubiquitination module, are required for deubiquitination of H2BK120ub following DNA damage, are critical for CSR, and function downstream of AID. The SAGA deubiquitinase activity was required for optimal irradiation-induced γH2AX formation, and failure to remove H2BK120ub inhibits ATM- and DNAPK-induced γH2AX formation. Consistent with this effect, these proteins were found to function upstream of various double-stranded DNA repair pathways. This report demonstrates that deubiquitination of histone H2B impacts the early stages of the DDR and is required for the DNA repair phase of CSR.