53BP1, BRCA1, and the Choice between Recombination and End Joining at DNA Double-Strand Breaks

Daley, James M.; Sung, Patrick

doi:10.1128/mcb.01639-13

Cited by 246 publications

(250 citation statements)

References 108 publications

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“…The role of BRCA1 and 53BP1 and associated partners in the choice of DNA repair pathway is an area of ongoing research. 34 Our results implicate CUPID1 and CUPID2 in this field, and future work should determine whether the lncRNAs directly affect DNA end resection, the relationship between 53BP1, RIF1, and PTIP and/or BRCA1 and CtIP at the DSB sites, and/or chromatin remodelling, particularly through histone modification around the DNA breaks. Alternatively, CUPID1 might be acting as an RNA scaffold for DNA-repair complexes similarly to LINP1, which has recently been shown to promote NHEJ by acting as a RNA scaffold for Ku70-Ku80 and DNA-PKcs.…”

Section: Discussionmentioning

confidence: 62%

Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage

Betts

Marjaneh

Al-Ejeh

et al. 2017

The American Journal of Human Genetics

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Breast cancer risk is strongly associated with an intergenic region on 11q13. We have previously shown that the strongest risk-associated SNPs fall within a distal enhancer that regulates CCND1. Here, we report that, in addition to regulating CCND1, this enhancer regulates two estrogen-regulated long noncoding RNAs, CUPID1 and CUPID2. We provide evidence that the risk-associated SNPs are associated with reduced chromatin looping between the enhancer and the CUPID1 and CUPID2 bidirectional promoter. We further show that CUPID1 and CUPID2 are predominantly expressed in hormone-receptor-positive breast tumors and play a role in modulating pathway choice for the repair of double-strand breaks. These data reveal a mechanism for the involvement of this region in breast cancer.

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Section: Discussionmentioning

confidence: 62%

Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage

Betts

Marjaneh

Al-Ejeh

et al. 2017

The American Journal of Human Genetics

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“…Intriguingly, emerging evidence highlights a key role of the tumor suppressor BRCA1 in maintaining the balance between HR-and non-homologous end joining-mediated DSB repair (21). This is accomplished, in part, by its ability to form distinct macromolecular protein assemblies (22).…”

Section: Resultsmentioning

confidence: 99%

The Lys63-deubiquitylating Enzyme BRCC36 Limits DNA Break Processing and Repair

Ng¹,

Wei

Lan

et al. 2016

Journal of Biological Chemistry

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Multisubunit protein assemblies offer integrated functionalities for efficient cell signal transduction control. One example of such protein assemblies, the BRCA1-A macromolecular complex, couples ubiquitin recognition and metabolism and promotes cellular responses to DNA damage. Specifically, the BRCA1-A complex not only recognizes Lys 63 -linked ubiquitin (K63-Ub) adducts at the damaged chromatin but is endowed with K63-Ub deubiquitylase (DUB) activity. To explore how the BRCA1-A DUB activity contributes to its function at DNA double strand breaks (DSBs), we used RNAi and genome editing approaches to target BRCC36, the protein subunit that confers the BRCA1-A complex its DUB activity. Intriguingly, we found that the K63-Ub DUB activity, although dispensable for maintaining the integrity of the macromolecular protein assembly, is important in enforcing the accumulation of the BRCA1-A complex onto DSBs. Inactivating BRCC36 DUB attenuated BRCA1-A functions at DSBs and led to unrestrained DSB end resection and hyperactive DNA repair. Together, our findings uncover a pivotal role of BRCC36 DUB in limiting DSB processing and repair and illustrate how cells may physically couple ubiquitin recognition and metabolizing activities for fine tuning of DNA repair processes. Active hydrolysis of ubiquitin polymers by deubiquitylases (DUBs)2 has emerged as important biochemical processes that underlie diverse signal transduction pathways, including cell responses to DNA damage (1). To date, around 94 human DUBs have been identified and are classified into five families: ubiquitin C-terminal hydrolases, ubiquitin-specific proteases, ovarian tumor proteases, Josephins, and JAB1/MPN/MOV4 metalloproteases. Notably, the JAB1/MPN/MOV4 metalloprotease family members are zinc-dependent metalloproteases, and the other families are cysteine proteases (1).BRCC36, originally reported as the BRCA1/BRCA2-containing complex subunit 36 (2), is endowed with DUB activity for lysine 63-linked ubiquitin polymers (K63-Ub). BRCC36 DUB relies on its zinc-dependent JAB1/MPN/MOV4 metalloprotease domain (3) and its interaction with Abraxas/KIAA0157 (3-5). Although BRCC36 forms distinct nuclear and cytoplasmic complexes (5, 6) and plays pleiotropic roles during cell proliferation, the K63-Ub DUB is arguably best known for its strong links with the breast and ovarian susceptible gene product BRCA1 in DNA damage responses (DDRs). Indeed, BRCC36 resides within the BRCA1-A macromolecular protein complex, which comprises the ubiquitin-binding protein RAP80, BRCC45/BRE, Abraxas/CCDC98, Merit40/NBA1, and BRCA1. The BRCA1-A complex is targeted to chromatin domains surrounding DNA double strand breaks (DSBs) by the ubiquitin-binding protein RAP80, which preferentially binds to K63-Ub adducts generated by the ubiquitin-conjugating enzyme UBC13 (3, 7-12). Abraxas plays a major scaffolding role to support the integrity of the BRCA1-A assembly and directly anchors the tumor suppressor BRCA1 via a phosphorylation-dependent interaction (13-15). Indeed, BRCA1, via it...

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“…One of these is integrated in chromosome V, whereas a second, 35-kb SinLoG, is excised from chromosome IX. DNA ends are highly recombinogenic and can interact directly with homologous sequences (21) and homologous recombination is the main double-strand break repair mechanism in growing S. cerevisiae (22,23). The excised SinLoG-IX, or fragments generated by unspecific nuclease activity, might recombine with the newly integrated SinLoG-V.…”

Section: Discussionmentioning

confidence: 99%

Pathway swapping: Toward modular engineering of essential cellular processes

Kuijpers

Solis-Escalante

Luttik

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Recent developments in synthetic biology enable one-step implementation of entire metabolic pathways in industrial microorganisms. A similarly radical remodelling of central metabolism could greatly accelerate fundamental and applied research, but is impeded by the mosaic organization of microbial genomes. To eliminate this limitation, we propose and explore the concept of "pathway swapping," using yeast glycolysis as the experimental model. Construction of a "single-locus glycolysis" Saccharomyces cerevisiae platform enabled quick and easy replacement of this yeast's entire complement of 26 glycolytic isoenzymes by any alternative, functional glycolytic pathway configuration. The potential of this approach was demonstrated by the construction and characterization of S. cerevisiae strains whose growth depended on two nonnative glycolytic pathways: a complete glycolysis from the related yeast Saccharomyces kudriavzevii and a mosaic glycolysis consisting of yeast and human enzymes. This work demonstrates the feasibility and potential of modular, combinatorial approaches to engineering and analysis of core cellular processes.pathway swapping | glycolysis | Saccharomyces cerevisiae | modular genomes R eplacement of petrochemistry by bio-based processes is a key element for sustainable development and requires microbes equipped with novel-to-nature capabilities. Recent developments in synthetic biology enable introduction of entire metabolic pathways and, thereby, new functionalities for product formation and substrate consumption, into microbial cells (1). However, industrial relevance of the resulting strains critically depends on optimal interaction of the newly introduced pathways with the core metabolism of the host cell. Central metabolic pathways such as glycolysis, tricarboxylic acid cycle, and pentose phosphate pathways, are essential for synthesis of precursors, for providing free energy (ATP), and for redox-cofactor balancing. Optimization of productivity, product yield, and robustness therefore requires modifications in the configuration and/or regulation of these core metabolic functions.Engineering of central metabolism is in some respects more challenging than the functional expression of heterologous product pathways. Millions of years of evolution of microorganisms have endowed their metabolic and regulatory networks with a level of complexity that cannot be efficiently reengineered by iterative, single-gene modifications. Enzymes of central metabolism are encoded by hundreds of genes that, especially in eukaryotes, are scattered across microbial genomes. Moreover, inactivation and subsequent replacement of genes involved in central metabolism is complicated by functional redundancy of isoenzymes (2, 3) as well as by the essential role of many of the corresponding biochemical reactions. Microbial platforms in which the configuration of key pathways can be remodelled in a swift, combinatorial manner would provide an invaluable asset for fundamental research and engineering of central metabolism.Wherea...

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53BP1, BRCA1, and the Choice between Recombination and End Joining at DNA Double-Strand Breaks

Cited by 246 publications

References 108 publications

Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage

Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage

The Lys63-deubiquitylating Enzyme BRCC36 Limits DNA Break Processing and Repair

Pathway swapping: Toward modular engineering of essential cellular processes

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