A PTIP-PA1 subcomplex promotes transcription for IgH class switching independently from the associated MLL3/MLL4 methyltransferase complex.
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.
['Starnes|Linda M|LM|', 'Su|Dan|D|', 'Pikkupeura|Laura M|LM|', 'Weinert|Brian T|BT|', 'Santos|Margarida A|MA|', 'Mund|Andreas|A|', 'Soria|Rebeca|R|', 'Cho|Young-Wook|YW|', 'Pozdnyakova|Irina|I|', 'Kubec Højfeldt|Martina|M|', 'Vala|Andrea|A|', 'Yang|Wenjing|W|', 'López-Méndez|Blanca|B|', 'Lee|Ji-Eun|JE|', 'Peng|Weiqun|W|', 'Yuan|Joan|J|', 'Ge|Kai|K|', 'Montoya|Guillermo|G|', 'Nussenzweig|André|A|', 'Choudhary|Chunaram|C|', 'Daniel|Jeremy A|JA|']
D002352:Carrier Proteins D004249:DNA Damage D004268:DNA-Binding Proteins D005786:Gene Expression Regulation D011495:Histone-Lysine N-Methyltransferase D017578:Immunoglobulin Class Switching D007143:Immunoglobulin Heavy Chains D015394:Molecular Structure D009687:Nuclear Proteins D017434:Protein Structure, Tertiary D021381:Protein Transport
DNA damage PTIP BRCT domains 53BP1 antigen receptor rearrangements histone methylation