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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 and Kubec Højfeldt, Martina, et al. (2016) In Genes & Development 30(2). p.149-163
Abstract
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... (More)
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. (Less)
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Genes & Development
volume
30
issue
2
pages
149 - 163
publisher
Cold Spring Harbor Laboratory Press
external identifiers
  • pmid:26744420
  • wos:000369124800002
  • scopus:84954538206
ISSN
1549-5477
DOI
10.1101/gad.268797.115
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English
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83b6fcbd-6bac-4bac-8475-388a6770bfef (old id 8592673)
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http://www.ncbi.nlm.nih.gov/pubmed/26744420?dopt=Abstract
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2016-02-02 09:21:16
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@article{83b6fcbd-6bac-4bac-8475-388a6770bfef,
  abstract     = {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.},
  author       = {Starnes, Linda M and Su, Dan and Pikkupeura, Laura M and Weinert, Brian T and Santos, Margarida A and Mund, Andreas and Soria, Rebeca and Cho, Young-Wook and Pozdnyakova, Irina and Kubec Højfeldt, Martina and Vala, Andrea and Yang, Wenjing and López-Méndez, Blanca and Lee, Ji-Eun and Peng, Weiqun and Yuan, Joan and Ge, Kai and Montoya, Guillermo and Nussenzweig, André and Choudhary, Chunaram and Daniel, Jeremy A},
  issn         = {1549-5477},
  language     = {eng},
  number       = {2},
  pages        = {149--163},
  publisher    = {Cold Spring Harbor Laboratory Press},
  series       = {Genes & Development},
  title        = {A PTIP-PA1 subcomplex promotes transcription for IgH class switching independently from the associated MLL3/MLL4 methyltransferase complex.},
  url          = {http://dx.doi.org/10.1101/gad.268797.115},
  volume       = {30},
  year         = {2016},
}