Systematic screening reveals a role for BRCA1 in the response to transcription-associated DNA damage

Hill, Sarah J.; Rolland, Thomas; Adelmant, Guillaume; Xia, Xianfang; Owen, Matthew; Dricot, Amélie; Zack, Travis I.; Sahni, Nidhi; Jacob, Yves; Hao, Tong; McKinney, Kristine; Clark, Allison; Reyon, Deepak; Tsai, Shengdar Q.; Joung, J. Keith; Beroukhim, Rameen; Marto, Jarrod A.; Vidal, Marc; Gaudet, Suzanne; Hill, David E.; Livingston, David M.

doi:10.1101/gad.241620.114

Cited by 91 publications

(88 citation statements)

References 72 publications

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“…If depletion of a protein leads to increased sensitivity to α-amanitin-induced transcription arrest, the protein of interest might be required for the prevention or repair of transcription arrest-driven DNA damage. Indeed, depletion of the tumor suppressor and DNA damage repair protein, BRCA1 (breast cancer 1), leads to increased α-amanitin sensitivity, and this effect is due to increased DNA damage (18). We detected multiple roles for BRCA1 in the prevention and repair of transcription-associated DNA damage, including in promoting the restart of transcription after UV arrest and preventing/repairing R loop-driven DNA damage (18).…”

Section: Depletion Of Fus and Tdp43 Leads To Excessive Transcription mentioning

confidence: 93%

“…S3B). A significant fraction of post-UV BRCA1-containing foci contained active RNA Pol II, γH2AX, and phosphorylated RPA, suggesting that a significant number of active RNA Pol II foci contain γH2AX and phosphorylated RPA and thus arose in association with transcription-associated DNA damage (18).…”

Section: Depletion Of Fus and Tdp43 Leads To Excessive Transcription mentioning

confidence: 99%

“…UV exposure induces the formation of active RNA Pol II-containing nuclear foci that contain certain DNA damage markers such as phosphorylated-RPA (replication protein A), γH2AX, and BRCA1 (18). One possibility is that these foci are active sites of transcription-associated DNA damage repair.…”

Section: Depletion Of Fus and Tdp43 Leads To Excessive Transcription mentioning

confidence: 99%

“…Indeed, depletion of the tumor suppressor and DNA damage repair protein, BRCA1 (breast cancer 1), leads to increased α-amanitin sensitivity, and this effect is due to increased DNA damage (18). We detected multiple roles for BRCA1 in the prevention and repair of transcription-associated DNA damage, including in promoting the restart of transcription after UV arrest and preventing/repairing R loop-driven DNA damage (18). Thus, given their transcription/RNA processing association, we asked whether cells depleted of FUS or TDP43 exhibit an increase in α-amanitin sensitivity.…”

Section: Depletion Of Fus and Tdp43 Leads To Excessive Transcription mentioning

confidence: 99%

“…To determine whether FUS localizes at sites of transcriptionassociated DNA damage, we searched for FUS at UV-induced DNA damage sites that are associated with transcription arrest (18,23). UV exposure induces the formation of active RNA Pol II-containing nuclear foci that contain certain DNA damage markers such as phosphorylated-RPA (replication protein A), γH2AX, and BRCA1 (18).…”

Section: Depletion Of Fus and Tdp43 Leads To Excessive Transcription mentioning

confidence: 99%

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Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage

Hill

Mordes

Cameron

et al. 2016

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

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107

119

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Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron dysfunction disease that leads to paralysis and death. There is currently no established molecular pathogenesis pathway. Multiple proteins involved in RNA processing are linked to ALS, including FUS and TDP43, and we propose a disease mechanism in which loss of function of at least one of these proteins leads to an accumulation of transcription-associated DNA damage contributing to motor neuron cell death and progressive neurological symptoms. In support of this hypothesis, we find that FUS or TDP43 depletion leads to increased sensitivity to a transcription-arresting agent due to increased DNA damage. Thus, these proteins normally contribute to the prevention or repair of transcription-associated DNA damage. In addition, both FUS and TDP43 colocalize with active RNA polymerase II at sites of DNA damage along with the DNA damage repair protein, BRCA1, and FUS and TDP43 participate in the prevention or repair of R loopassociated DNA damage, a manifestation of aberrant transcription and/or RNA processing. Gaining a better understanding of the role(s) that FUS and TDP43 play in transcription-associated DNA damage could shed light on the mechanisms underlying ALS pathogenesis.A myotrophic lateral sclerosis (ALS) is a disease of both upper and lower motor neuron dysfunction that leads to progressive paralysis and eventually death due to respiratory failure. No single model of ALS disease pathogenesis has been revealed; however, multiple disease-associated genes are known (1). The variation in function of these genes suggests that there may be multiple ALS molecular subtypes. That said, the familial ALS gene product list is also enriched in protein groups with related functions.Mutations in multiple RNA processing genes, including FUS (FUS RNA-binding protein), TDP43 (TAR DNA-binding protein), SETX (senataxin), TAF15 (TATA box-binding protein-associated factor 15), EWSR1 (EWS RNA-binding protein 1), HNRNPA1 (heterogeneous nuclear ribonucleoprotein A1), and HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1), among others, give rise to familial ALS (fALS) (1). FUS and TDP43 are currently the best studied, given that mutations in these genes lead to classic histologic findings in ALS neural tissue and that similar histologic findings can be found in neural tissue of sporadic ALS cases (2). At autopsy, cytoplasmic TDP43 inclusions are found in ALS motor neurons from patients with (i) TDP43 mutations and (ii) sporadic ALS (i.e., patients with no FUS, TDP43, or other known pathogenic mutation) (2). They are also present in neurons in various parts of the brains of patients with either sporadic or familial versions of the ALS-related disorder, fronto-temporal lobar dementia (FTLD) (2). At autopsy, FUS inclusions were detected in the cytoplasm of motor neurons of FUS mutation-bearing fALS patients and in the cytoplasm of neurons in various regions of the brain in some FTLD patients (2).FUS and TDP43 exhibit a wide range of functions, most of which involv...

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Section: Depletion Of Fus and Tdp43 Leads To Excessive Transcription mentioning

confidence: 93%

Section: Depletion Of Fus and Tdp43 Leads To Excessive Transcription mentioning

confidence: 99%

Section: Depletion Of Fus and Tdp43 Leads To Excessive Transcription mentioning

confidence: 99%

Section: Depletion Of Fus and Tdp43 Leads To Excessive Transcription mentioning

confidence: 99%

Section: Depletion Of Fus and Tdp43 Leads To Excessive Transcription mentioning

confidence: 99%

See 3 more Smart Citations

Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage

Hill

Mordes

Cameron

et al. 2016

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

Self Cite

107

119

View full text Add to dashboard Cite

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Small‐molecule Effectors of DNA Repair Proteins: Applications for Development of Cancer Therapeutics and Research

Chheda

Spies

2021

Burger's Medicinal Chemistry and Drug Discovery

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A ubiquitous aspect of cellular life is the need to repair the many deleterious DNA lesions that arise due to environmental damage and as byproducts of normal cellular metabolism. The same DNA repair processes, which are critical for life, are also employed by cancer cells in their resistance to radiation and DNA‐damaging therapies. Inhibition of DNA repair or entrapment of the toxic DNA repair intermediates with the help of small molecules has both potential therapeutic and research utility. Although many proteins that maintain genome integrity and repair DNA damage appear to be attractive targets, they lack well‐defined small‐molecule binding determinants and clear structure–activity relationships. This article summarizes a number of studies that have led to the identification of small‐molecule drug lead compounds, which may also be useful in dissecting complex DNA repair networks. Systems that are particularly noteworthy are inhibition of PARP1, as it is a paradigm case for achieving successful clinical applications, and the emerging targets RAD51 recombinase, RAD52 DNA repair protein, MRE11 nuclease, and WRN DNA helicase.

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CWF19L2 is Essential for Male Fertility and Spermatogenesis by Regulating Alternative Splicing

Wang,

Cai,

et al. 2024

Advanced Science

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The progression of spermatogenesis along specific developmental trajectories depends on the coordinated regulation of pre‐mRNA alternative splicing (AS) at the post‐transcriptional level. However, the fundamental mechanism of AS in spermatogenesis remains to be investigated. Here, it is demonstrated that CWF19L2 plays a pivotal role in spermatogenesis and male fertility. In germline conditional Cwf19l2 knockout mice exhibiting male sterility, impaired spermatogenesis characterized by increased apoptosis and decreased differentiated spermatogonia and spermatocytes is observed. That CWF19L2 interacted with several spliceosome proteins to participate in the proper assembly and stability of the spliceosome is discovered. By integrating RNA‐seq and LACE‐seq data, it is further confirmed CWF19L2 directly bound and regulated the splicing of genes related to spermatogenesis (Znhit1, Btrc, and Fbxw7) and RNA splicing (Rbfox1, Celf1, and Rbm10). Additionally, CWF19L2 can indirectly amplify its effect on splicing regulation through modulating RBFOX1. Collectively, this research establishes that CWF19L2 orchestrates a splicing factor network to ensure accurate pre‐mRNA splicing during the early steps of spermatogenesis.

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Systematic screening reveals a role for BRCA1 in the response to transcription-associated DNA damage

Cited by 91 publications

References 72 publications

Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage

Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage

Small‐molecule Effectors of DNA Repair Proteins: Applications for Development of Cancer Therapeutics and Research

CWF19L2 is Essential for Male Fertility and Spermatogenesis by Regulating Alternative Splicing

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