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1.
Mol Cell ; 84(18): 3375-3377, 2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-39303678

RESUMO

In this issue of Molecular Cell, De La Cruz, Pradhan, Veettil et al.1 examine how selective partitioning of proteins via low-affinity IDR-dependent interactions may help regulate RNA polymerase II (RNA Pol II) function and identify sequence features that drive partitioning in cells.


Assuntos
RNA Polimerase II , Transcrição Gênica , RNA Polimerase II/metabolismo , RNA Polimerase II/genética , Regulação da Expressão Gênica , Humanos , Ligação Proteica , Proteínas Intrinsicamente Desordenadas/metabolismo , Proteínas Intrinsicamente Desordenadas/química , Proteínas Intrinsicamente Desordenadas/genética
2.
Mol Cell ; 81(24): 4994-5006.e5, 2021 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-34919819

RESUMO

PARP1 is a key player in the response to DNA damage and is the target of clinical inhibitors for the treatment of cancers. Binding of PARP1 to damaged DNA leads to activation wherein PARP1 uses NAD+ to add chains of poly(ADP-ribose) onto itself and other nuclear proteins. PARP1 also binds abundantly to intact DNA and chromatin, where it remains enzymatically inactive. We show that intact DNA makes contacts with the PARP1 BRCT domain, which was not previously recognized as a DNA-binding domain. This binding mode does not result in the concomitant reorganization and activation of the catalytic domain. We visualize the BRCT domain bound to nucleosomal DNA by cryogenic electron microscopy and identify a key motif conserved from ancestral BRCT domains for binding phosphates on DNA and phospho-peptides. Finally, we demonstrate that the DNA-binding properties of the BRCT domain contribute to the "monkey-bar mechanism" that mediates DNA transfer of PARP1.


Assuntos
Dano ao DNA , DNA/metabolismo , Nucleossomos/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Animais , Células Cultivadas , DNA/genética , DNA/ultraestrutura , Fibroblastos/enzimologia , Humanos , Camundongos , Modelos Moleculares , Mutação , Conformação de Ácido Nucleico , Nucleossomos/genética , Nucleossomos/ultraestrutura , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/ultraestrutura , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas
3.
J Mol Biol ; 434(1): 167216, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34474085

RESUMO

The regulation of RNA polymerase II (pol II) transcription requires a complex and context-specific array of proteins and protein complexes, as well as nucleic acids and metabolites. Every major physiological process requires coordinated transcription of specific sets of genes at the appropriate time, and a breakdown in this regulation is a hallmark of human disease. A proliferation of recent studies has revealed that many general transcription components, including sequence-specific, DNA-binding transcription factors, Mediator, and pol II itself, are capable of liquid-liquid phase separation, to form condensates that partition these factors away from the bulk aqueous phase. These findings hold great promise for next-level understanding of pol II transcription; however, many mechanistic aspects align with more conventional models, and whether phase separation per se regulates pol II activity in cells remains controversial. In this review, we describe the conventional and condensate-dependent models, and why their similarities and differences are important. We also compare and contrast these models in the context of genome organization and pol II transcription (initiation, elongation, and termination), and highlight the central role of RNA in these processes. Finally, we discuss mutations that disrupt normal partitioning of transcription factors, and how this may contribute to disease.


Assuntos
RNA Polimerase II/genética , RNA Polimerase II/metabolismo , RNA/química , Transcrição Gênica , Fenômenos Biofísicos , Núcleo Celular/química , Núcleo Celular/genética , Genoma Humano , Humanos , Mutação , RNA/genética , RNA/metabolismo , RNA Polimerase II/química , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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