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BRCT domains: easy as one, two, three.

ABSTRACT: BRCA1 C-terminal (BRCT) domains are integral signaling modules in the DNA damage response (DDR). Aside from their established roles as phospho-peptide binding modules, BRCT domains have been implicated in phosphorylation-independent protein interactions, DNA binding and poly(ADP-ribose) (PAR) binding. These numerous functions can be attributed to the diversity in BRCT domain structure and architecture, where domains can exist as isolated single domains or assemble into higher order homo- or hetero- domain complexes. In this review, we incorporate recent structural and biochemical studies to demonstrate how structural features allow single and tandem BRCT domains to attain a high degree of functional diversity.

SUBMITTER: Leung CC

PROVIDER: S-EPMC3180187 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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BRCT domains: easy as one, two, three.

Leung Charles Chung Yun CC Glover J N Mark JN

Cell cycle (Georgetown, Tex.) 20110801 15

BRCA1 C-terminal (BRCT) domains are integral signaling modules in the DNA damage response (DDR). Aside from their established roles as phospho-peptide binding modules, BRCT domains have been implicated in phosphorylation-independent protein interactions, DNA binding and poly(ADP-ribose) (PAR) binding. These numerous functions can be attributed to the diversity in BRCT domain structure and architecture, where domains can exist as isolated single domains or assemble into higher order homo- or hete ...[more]

PMID: 21734457

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TopBP1 contains a transcriptional activation domain suppressed by two adjacent BRCT domains.

Project description:TopBP1 has eight BRCT [BRCA1 (breast-cancer susceptibility gene 1) C-terminus] domains and is involved in initiating DNA replication, and DNA damage checkpoint signalling and repair. Several BRCT-domain-containing proteins involved in mediating DNA repair have transcriptional regulatory domains, and as demonstrated for BRCA1 these regulatory domains are important in mediating the functions of these proteins. These transcriptional regulatory processes involve modification of chromatin, and recent evidence has clearly demonstrated that the ability to modify chromatin plays an important role in regulating DNA damage signalling and repair. Here we report the identification of a TopBP1 transcriptional activation domain that is rich in hydrophobic residues, interspersed with acidic amino acids, characteristics that are typical of transcriptional activation domains identified previously. Two adjacent repressor domains encoded by BRCT2 and BRCT5 silence this activator and experiments suggest that these repressors actively recruit repressor complexes. Both the activator and BRCT2 repressor domains function in yeast. The present study identifies several chromatin modification domains encoded by TopBP1, and the implications of these findings are discussed in the context of the DNA damage response and the understanding of TopBP1 function.

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Tandem BRCT Domains: DNA's Praetorian Guard.

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Functional Evolution of BRCT Domains from Binding DNA to Protein.

Project description:The BRCT domain (BRCA1 C-terminal domain) is an important signaling and protein targeting motif in the DNA damage response system. The BRCT domain, which mainly occurs as a singleton (single BRCT) or tandem pair (double BRCT), contains a phosphate-binding pocket that can bind the phosphate from either the DNA end or a phosphopeptide. In this work, we performed a database search, phylogeny reconstruction, and phosphate-binding pocket comparison to analyze the functional evolution of the BRCT domain. We identified new BRCT-containing proteins in bacteria and eukaryotes, and found that the number of BRCT-containing proteins per genome is correlated with genome complexity. Phylogeny analyses revealed that there are two groups of single BRCT domains (sGroup I and sGroup II) and double BRCT domains (dGroup I and dGroup II). These four BRCT groups differ in their phosphate-binding pockets. In eukaryotes, the evolution of the BRCT domain can be divided into three phases. In the first phase, the sGroup I BRCT domain with the phosphate-binding pocket that can bind the phosphate of nicked DNA invaded eukaryotic genome. In the second phase, the phosphate-binding pocket changed from a DNA-binding type to a protein-binding type in sGroup II. The tandem duplication of sGroup II BRCT domain gave birth to double BRCT domain, from which two structurally and functionally distinct groups were evolved. The third phase is after the divergence between animals and plants. Both sGroup I and sGroup II BRCT domains originating in this phase lost the phosphate-binding pocket and many evolved protein-binding sites. Many dGroup I members were evolved in this stage but few dGroup II members were observed. The results further suggested that the BRCT domain expansion and functional change in eukaryote may be driven by the evolution of the DNA damage response system.

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Structural basis of BACH1 phosphopeptide recognition by BRCA1 tandem BRCT domains.

Project description:BRCT tandem domains, found in many proteins involved in DNA damage checkpoint and DNA repair pathways, were recently shown to be phosphopeptide binding motifs. Using solution nuclear magnetic resonance (NMR) spectroscopy and mutational analysis, we have characterized the interaction of BRCA1-BRCT domains with a phosphoserine-containing peptide derived from the DNA repair helicase BACH1. We show that a phenylalanine in the +3 position from the phosphoserine of BACH1 is bound to a conserved hydrophobic pocket formed between the two BRCT domains and that recognition of the phosphate group is mediated by lysine and serine side chains from the amino-terminal BRCT domain. Mutations that prevent phosphopeptide binding abolish BRCA1 function in DNA damage-induced checkpoint control. Our NMR data also reveal a dynamic interaction between BRCA1-BRCT and BACH1, where the bound phosphopeptide exists as an equilibrium of two conformations and where BRCA1-BRCT undergoes a transition to a more rigid conformation upon peptide binding.

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A comparison of BRCT domains involved in nonhomologous end-joining: introducing the solution structure of the BRCT domain of polymerase lambda.

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