A PTIP-PA1 subcomplex promotes transcription for IgH class switching independently from the associated MLL3/MLL4 methyltransferase complex.
A PTIP-PA1 subcomplex promotes transcription for IgH class switching independently from the associated MLL3/MLL4 methyltransferase complex.
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DOI：
10.1101/gad.268797.115
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发表时间：
2016-01-15
影响因子：
10.5
通讯作者：
Daniel JA
中科院分区：
文献类型：
--
作者：
Starnes LM;Su D;Pikkupeura LM;Weinert BT;Santos MA;Mund A;Soria R;Cho YW;Pozdnyakova I;Kubec Højfeldt M;Vala A;Yang W;López-Méndez B;Lee JE;Peng W;Yuan J;Ge K;Montoya G;Nussenzweig A;Choudhary C;Daniel JA
免疫球蛋白重链（Igh）基因座的转录靶向类别转换重组（CSR）相关的DNA损伤，并由含BRCT结构域的PTIP蛋白促进。Starnes等人发现PTIP在转录和CSR中的功能与其与MLL 3/MLL 4复合物的结合以及其定位于DNA损伤位点分开。类别转换重组（CSR）使抗体多样化，以产生免疫应答，同时保持B细胞基因组的稳定性。免疫球蛋白重链（Igh）位点的转录靶向CSR相关的DNA损伤，并由含有BRCT结构域的PTIP（Pax反式激活结构域相互作用蛋白）促进。虽然PTIP是混合谱系白血病3（MLL 3）/MLL 4染色质修饰复合物的独特组分，但PTIP如何促进转录的机制仍不清楚。在这里，我们解剖的最低结构要求的PTIP及其不同的蛋白质复合物，在初级淋巴细胞中使用定量蛋白质组学。我们发现PTIP在转录和CSR中的功能与其与MLL 3/MLL 4复合物的结合以及其定位于DNA损伤位点分开。我们确定了PTIP的串联BRCT结构域，足以进行CSR，并确定PA 1为其主要功能蛋白伴侣。总的来说，我们提供了遗传和生化证据表明PTIP-PA 1亚复合物的功能独立于MLL 3/MLL 4复合物，以介导CSR期间的转录。这些结果进一步加深了我们对多功能染色质修饰复合物如何由具有独特和独特活性的亚复合物组织的理解。
Transcription at the immunoglobulin heavy chain (Igh) locus targets class switch recombination (CSR)-associated DNA damage and is promoted by the BRCT domain-containing PTIP protein. Starnes et al. found that PTIP functions in transcription and CSR separately from its association with the MLL3/MLL4 complex and from its localization to sites of DNA damage. Class switch recombination (CSR) diversifies antibodies for productive immune responses while maintaining stability of the B-cell genome. Transcription at the immunoglobulin heavy chain (Igh) locus targets CSR-associated DNA damage and is promoted by the BRCT domain-containing PTIP (Pax transactivation domain-interacting protein). Although PTIP is a unique component of the mixed-lineage leukemia 3 (MLL3)/MLL4 chromatin-modifying complex, the mechanisms for how PTIP promotes transcription remain unclear. Here we dissected the minimal structural requirements of PTIP and its different protein complexes using quantitative proteomics in primary lymphocytes. We found that PTIP functions in transcription and CSR separately from its association with the MLL3/MLL4 complex and from its localization to sites of DNA damage. We identified a tandem BRCT domain of PTIP that is sufficient for CSR and identified PA1 as its main functional protein partner. Collectively, we provide genetic and biochemical evidence that a PTIP–PA1 subcomplex functions independently from the MLL3/MLL4 complex to mediate transcription during CSR. These results further our understanding of how multifunctional chromatin-modifying complexes are organized by subcomplexes that harbor unique and distinct activities.