A PTIP-PA1 subcomplex promotes transcription for IgH class switching independently from the associated MLL3/MLL4 methyltransferase complex

TY - JOUR

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

SN - 0890-9369

VL - 30

SP - 149

EP - 163

JO - Genes & Development

JF - Genes & Development

IS - 2

ER -