A PTIP-PA1 subcomplex promotes transcription for IgH class switching independently from the associated MLL3/MLL4 methyltransferase complex
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A PTIP-PA1 subcomplex promotes transcription for IgH class switching independently from the associated MLL3/MLL4 methyltransferase complex. / Starnes, Linda M; Su, Dan; Pikkupeura, Laura M; Weinert, Brian T; Santos, Margarida A; Mund, Andreas; Soria, Rebeca; Cho, Young-Wook; Pozdnyakova, Irina; Kubec Højfeldt, Martina; Lages Lino Vala, Andrea; Yang, Wenjing; López-Méndez, Blanca; Lee, Ji-Eun; Peng, Weiqun; Yuan, Joan; Ge, Kai; Montoya, Guillermo; Nussenzweig, André; Choudhary, Chuna Ram; Daniel, Jeremy A.
In: Genes & Development, Vol. 30, No. 2, 15.01.2016, p. 149-163.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - A PTIP-PA1 subcomplex promotes transcription for IgH class switching independently from the associated MLL3/MLL4 methyltransferase complex
AU - Starnes, Linda M
AU - Su, Dan
AU - Pikkupeura, Laura M
AU - Weinert, Brian T
AU - Santos, Margarida A
AU - Mund, Andreas
AU - Soria, Rebeca
AU - Cho, Young-Wook
AU - Pozdnyakova, Irina
AU - Kubec Højfeldt, Martina
AU - Lages Lino Vala, Andrea
AU - Yang, Wenjing
AU - López-Méndez, Blanca
AU - Lee, Ji-Eun
AU - Peng, Weiqun
AU - Yuan, Joan
AU - Ge, Kai
AU - Montoya, Guillermo
AU - Nussenzweig, André
AU - Choudhary, Chuna Ram
AU - Daniel, Jeremy A
N1 - © 2016 Starnes et al.; Published by Cold Spring Harbor Laboratory Press.
PY - 2016/1/15
Y1 - 2016/1/15
N2 - 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.
AB - 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.
U2 - 10.1101/gad.268797.115
DO - 10.1101/gad.268797.115
M3 - Journal article
C2 - 26744420
VL - 30
SP - 149
EP - 163
JO - Genes & Development
JF - Genes & Development
SN - 0890-9369
IS - 2
ER -
ID: 154184612