Understanding the functions of BRCA1 in the DNA-damage response

2009 ◽  
Vol 37 (3) ◽  
pp. 597-604 ◽  
Author(s):  
Maximina H. Yun ◽  
Kevin Hiom
Keyword(s):  
Dna Damage ◽  
Early Onset ◽  
Genome Stability ◽  
Chromosomal Rearrangements ◽  
Dna Lesions ◽  
Cell Cycle Checkpoints ◽  
Dna Breaks ◽  
Gross Chromosomal Rearrangements ◽  
Damage Response ◽  
Regulation Of Cell Cycle

Inheritance of a mutation in BRCA1 (breast cancer 1 early-onset) results in predisposition to early-onset breast and ovarian cancer. Tumours in these individuals arise after somatic mutation or loss of the wild-type allele. Loss of BRCA1 function leads to a profound increase in genomic instability involving the accumulation of mutations, DNA breaks and gross chromosomal rearrangements. Accordingly, BRCA1 has been implicated as an important factor involved in both the repair of DNA lesions and in the regulation of cell-cycle checkpoints in response to DNA damage. However, the molecular mechanism through which BRCA1 functions to preserve genome stability remains unclear. In the present article, we examine the different ways in which BRCA1 might influence the repair of DNA damage and the preservation of genome integrity, taking into account what is currently known about its interactions with other proteins, its biochemical activity and its nuclear localization.

scholarly journals 53BP1 mediated recruitment of RASSF1A at ribosomal DNA breaks facilitates local ATM signal amplification

2021 ◽  
Author(s):  
Stavroula Tsaridou ◽  
Georgia Velimezi ◽  
Frances Willenbrock ◽  
Maria Chatzifrangkeskou ◽  
Andreas Panagopoulos ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Viability ◽  
Copy Number ◽  
Adaptor Proteins ◽  
Fragile Sites ◽  
Dna Lesions ◽  
Dna Breaks ◽  
Damage Response ◽  
Rdna Copy ◽  
Rdna Copy Number

DNA lesions occur across the genome and constitute a threat to cell viability; however, damage at specific genomic loci has a disproportionally greater impact on the overall genome stability. The ribosomal RNA gene repeats (rDNA) are emerging fragile sites due to repetitive nature, clustering and high transcriptional activity. Recent progress in understanding how the rDNA damage response is organized has highlighted the key role of adaptor proteins in the response. Here we identify that the scaffold and tumor suppressor, RASSF1A is recruited at sites of damage and enriched at rDNA breaks. Employing targeted nucleolar DNA damage, we find that RASSF1A recruitment requires ATM activity and depends on 53BP1. At sites of damage RASSF1A facilitates local ATM signal establishment and rDNA break repair. RASSF1A silencing, a common epigenetic event during malignant transformation, results in persistent breaks, rDNA copy number alterations and decreased cell viability. Meta-analysis of a lung adenocarcinoma cohort showed that RASSF1A epigenetic silencing leads in rDNA copy number discrepancies. Overall, we present evidence that RASSF1A acts as a DNA repair factor and offer mechanistic insight in how the nucleolar DNA damage response is organized.

scholarly journals DDB1 Maintains Genome Integrity through Regulation of Cdt1

2006 ◽  
Vol 26 (21) ◽  
pp. 7977-7990 ◽  
Author(s):  
Courtney A. Lovejoy ◽  
Kimberli Lock ◽  
Ashwini Yenamandra ◽  
David Cortez
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Genome Instability ◽  
Excision Repair ◽  
Dna Lesions ◽  
Cell Cycle Checkpoints ◽  
Dna Double Strand Breaks ◽  
Genome Maintenance ◽  
Strand Breaks ◽  
Ubiquitin Ligase Complex

ABSTRACT DDB1, a component of a Cul4A ubiquitin ligase complex, promotes nucleotide excision repair (NER) and regulates DNA replication. We have investigated the role of human DDB1 in maintaining genome stability. DDB1-depleted cells accumulate DNA double-strand breaks in widely dispersed regions throughout the genome and have activated ATM and ATR cell cycle checkpoints. Depletion of Cul4A yields similar phenotypes, indicating that an E3 ligase function of DDB1 is important for genome maintenance. In contrast, depletion of DDB2, XPA, or XPC does not cause activation of DNA damage checkpoints, indicating that defects in NER are not involved. One substrate of DDB1-Cul4A that is crucial for preventing genome instability is Cdt1. DDB1-depleted cells exhibit increased levels of Cdt1 protein and rereplication, despite containing other Cdt1 regulatory mechanisms. The rereplication, accumulation of DNA damage, and activation of checkpoint responses in DDB1-depleted cells require entry into S phase and are partially, but not completely, suppressed by codepletion of Cdt1. Therefore, DDB1 prevents DNA lesions from accumulating in replicating human cells, in part by regulating Cdt1 degradation.

scholarly journals Involvement of DNA Damage Response Pathways in Hepatocellular Carcinoma

2014 ◽  
Vol 2014 ◽  
pp. 1-18 ◽  
Author(s):  
Sheau-Fang Yang ◽  
Chien-Wei Chang ◽  
Ren-Jie Wei ◽  
Yow-Ling Shiue ◽  
Shen-Nien Wang ◽  
...  
Keyword(s):  
Risk Factors ◽  
Hepatocellular Carcinoma ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Genetic Alterations ◽  
Dna Lesions ◽  
Cell Cycle Checkpoints ◽  
Dna Damages ◽  
Damage Response ◽  
Associated Risk Factors

Hepatocellular carcinoma (HCC) has been known as one of the most lethal human malignancies, due to the difficulty of early detection, chemoresistance, and radioresistance, and is characterized by active angiogenesis and metastasis, which account for rapid recurrence and poor survival. Its development has been closely associated with multiple risk factors, including hepatitis B and C virus infection, alcohol consumption, obesity, and diet contamination. Genetic alterations and genomic instability, probably resulted from unrepaired DNA lesions, are increasingly recognized as a common feature of human HCC. Dysregulation of DNA damage repair and signaling to cell cycle checkpoints, known as the DNA damage response (DDR), is associated with a predisposition to cancer and affects responses to DNA-damaging anticancer therapy. It has been demonstrated that various HCC-associated risk factors are able to promote DNA damages, formation of DNA adducts, and chromosomal aberrations. Hence, alterations in the DDR pathways may accumulate these lesions to trigger hepatocarcinogenesis and also to facilitate advanced HCC progression. This review collects some of the most known information about the link between HCC-associated risk factors and DDR pathways in HCC. Hopefully, the review will remind the researchers and clinicians of further characterizing and validating the roles of these DDR pathways in HCC.

scholarly journals Inactivation of folylpolyglutamate synthetase Met7 results in genome instability driven by an increased dUTP/dTTP ratio

2019 ◽  
Author(s):  
Tobias T Schmidt ◽  
Sushma Sharma ◽  
Gloria X Reyes ◽  
Anna Kolodziejczak ◽  
Tina Wagner ◽  
...  
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Nuclear Dna ◽  
Genome Instability ◽  
Chromosomal Rearrangements ◽  
Dna Integrity ◽  
Folylpolyglutamate Synthetase ◽  
Cell Extracts ◽  
Gross Chromosomal Rearrangements ◽  
The Stability

Abstract The accumulation of mutations is frequently associated with alterations in gene function leading to the onset of diseases, including cancer. Aiming to find novel genes that contribute to the stability of the genome, we screened the Saccharomyces cerevisiae deletion collection for increased mutator phenotypes. Among the identified genes, we discovered MET7, which encodes folylpolyglutamate synthetase (FPGS), an enzyme that facilitates several folate-dependent reactions including the synthesis of purines, thymidylate (dTMP) and DNA methylation. Here, we found that Met7-deficient strains show elevated mutation rates, but also increased levels of endogenous DNA damage resulting in gross chromosomal rearrangements (GCRs). Quantification of deoxyribonucleotide (dNTP) pools in cell extracts from met7Δ mutant revealed reductions in dTTP and dGTP that cause a constitutively active DNA damage checkpoint. In addition, we found that the absence of Met7 leads to dUTP accumulation, at levels that allowed its detection in yeast extracts for the first time. Consequently, a high dUTP/dTTP ratio promotes uracil incorporation into DNA, followed by futile repair cycles that compromise both mitochondrial and nuclear DNA integrity. In summary, this work highlights the importance of folate polyglutamylation in the maintenance of nucleotide homeostasis and genome stability.

Histone marks: repairing DNA breaks within the context of chromatin

2012 ◽  
Vol 40 (2) ◽  
pp. 370-376 ◽  
Author(s):  
Kyle M. Miller ◽  
Stephen P. Jackson
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genome Stability ◽  
Nuclear Dna ◽  
Dna Lesions ◽  
Dna Breaks ◽  
Strand Breaks ◽  
Dna Dsbs

Inherited or acquired defects in detecting, signalling or repairing DNA damage are associated with various human pathologies, including immunodeficiencies, neurodegenerative diseases and various forms of cancer. Nuclear DNA is packaged into chromatin and therefore the true in vivo substrate of damaged DNA occurs within the context of chromatin. Our work aims to decipher the mechanisms by which cells detect DNA damage and signal its presence to the DNA-repair and cell-cycle machineries. In particular, much of our work has focused on DNA DSBs (double-strand breaks) that are generated by ionizing radiation and radiomimetic chemicals, and which can also arise when the DNA replication apparatus encounters other DNA lesions. In the present review, we describe some of our recent work, as well as the work of other laboratories, that has identified new chromatin proteins that mediate DSB responses, control SDB processing or modulate chromatin structure at DNA-damage sites. We also aim to survey several recent advances in the field that have contributed to our understanding of how particular histone modifications and involved in DNA repair. It is our hope that by understanding the role of chromatin and its modifications in promoting DNA repair and genome stability, this knowledge will provide opportunities for developing novel classes of drugs to treat human diseases, including cancer.

scholarly journals Gross chromosomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivation

2000 ◽  
Vol 14 (11) ◽  
pp. 1400-1406 ◽  
Author(s):  
Veronica P.C.C. Yu ◽  
Michael Koehler ◽  
Claus Steinlein ◽  
Michael Schmid ◽  
Leslyn A. Hanakahi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Genetic Instability ◽  
Genomic Dna ◽  
Chromosomal Rearrangements ◽  
Chromosome Breakage ◽  
Genetic Exchange ◽  
Dna Breaks ◽  
Gross Chromosomal Rearrangements ◽  
Essential Function ◽  
Mechanistic Basis

Cancer-causing mutations often arise from gross chromosomal rearrangements (GCRs) such as translocations, which involve genetic exchange between nonhomologous chromosomes. Here we show that murineBrca2 has an essential function in suppressing GCR formation after chromosome breakage. Cells that harbor truncated Brca2spontaneously incur GCRs and genomic DNA breaks during division. They exhibit hypersensitivity to DNA damage by interstrand cross-linkers, which even at low doses trigger aberrant genetic exchange between nonhomologous chromosomes. Therefore, genetic instability in Brca2-deficient cells results from the mutagenic processing of spontaneous or induced DNA damage into gross chromosomal rearrangements, providing a mechanistic basis for cancer predisposition.

scholarly journals Cdc28/Cdk1 positively and negatively affects genome stability in S. cerevisiae

2009 ◽  
Vol 185 (3) ◽  
pp. 423-437 ◽  
Author(s):  
Jorrit M. Enserink ◽  
Hans Hombauer ◽  
Meng-Er Huang ◽  
Richard D. Kolodner
Keyword(s):  
Dna Damage ◽  
Cell Viability ◽  
Genome Stability ◽  
Chromosomal Rearrangements ◽  
Genetic Network ◽  
Telomere Maintenance ◽  
Mitotic Catastrophe ◽  
Chemical Genetic ◽  
Replication Arrest ◽  
Gross Chromosomal Rearrangements

We studied the function of the cyclin-dependent kinase Cdc28 (Cdk1) in the DNA damage response and maintenance of genome stability using Saccharomyces cerevisiae. Reduced Cdc28 activity sensitizes cells to chronic DNA damage, but Cdc28 is not required for cell viability upon acute exposure to DNA-damaging agents. Cdc28 is also not required for activation of the DNA damage and replication checkpoints. Chemical–genetic analysis reveals that CDC28 functions in an extensive network of pathways involved in maintenance of genome stability, including homologous recombination, sister chromatid cohesion, the spindle checkpoint, postreplication repair, and telomere maintenance. In addition, Cdc28 and Mre11 appear to cooperate to prevent mitotic catastrophe after DNA replication arrest. We show that reduced Cdc28 activity results in suppression of gross chromosomal rearrangements (GCRs), indicating that Cdc28 is required for formation or recovery of GCRs. Thus, we conclude that Cdc28 functions in a genetic network that supports cell viability during DNA damage while promoting the formation of GCRs.

scholarly journals ADAR2-mediated RNA editing of DNA:RNA hybrids is required for DNA double strand break repair

2021 ◽  
Author(s):  
Sonia Jimeno ◽  
Rosario Prados-Carvajal ◽  
Maria Jesus Fernandez-Avila ◽  
Sonia Silva ◽  
Domenico Alessandro Silvestris ◽  
...  
Keyword(s):  
Dna Damage ◽  
Rna Editing ◽  
Genomic Stability ◽  
Strand Break ◽  
Dna Lesions ◽  
Dna Breaks ◽  
Dna Double Strand Break ◽  
Damage Response ◽  
Editing Enzyme

The maintenance of genomic stability requires the coordination of multiple cellular tasks upon the appearance of DNA lesions. RNA editing, the post-transcriptional sequence alteration of RNA, has a profound effect on cell homeostasis, but its implication in the response to DNA damage was not previously explored. Here we show that, in response to DNA breaks, an overall change of the Adenosine-to-Inosine RNA editing is observed, a phenomenon we call the RNA Editing DAmage Response (REDAR). REDAR relies on the checkpoint kinase ATR and the recombination factor CtIP. Moreover, depletion of the RNA editing enzyme ADAR2 renders cells hypersensitive to genotoxic agents, increases genomic instability and hampers homologous recombination by impairing DNA resection. Such a role of ADAR2 in DNA repair goes beyond the recoding of specific transcripts, but depends on ADAR2 editing DNA:RNA hybrids to ease their dissolution.

scholarly journals The DNA damage inducible lncRNA SCAT7 regulates genomic integrity and topoisomerase 1 turnover in lung adenocarcinoma

NAR Cancer ◽  
2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Luisa Statello ◽  
Mohamad M Ali ◽  
Silke Reischl ◽  
Sagar Mahale ◽  
Subazini Thankaswamy Kosalai ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cancer Biology ◽  
Topoisomerase I ◽  
Cell Cycle Checkpoints ◽  
Topoisomerase 1 ◽  
Damage Response ◽  
Promote Cell Survival

Abstract Despite the rapid improvements in unveiling the importance of lncRNAs in all aspects of cancer biology, there is still a void in mechanistic understanding of their role in the DNA damage response. Here we explored the potential role of the oncogenic lncRNA SCAT7 (ELF3-AS1) in the maintenance of genome integrity. We show that SCAT7 is upregulated in response to DNA-damaging drugs like cisplatin and camptothecin, where SCAT7 expression is required to promote cell survival. SCAT7 silencing leads to decreased proliferation of cisplatin-resistant cells in vitro and in vivo through interfering with cell cycle checkpoints and DNA repair molecular pathways. SCAT7 regulates ATR signaling, promoting homologous recombination. Importantly, SCAT7 also takes part in proteasome-mediated topoisomerase I (TOP1) degradation, and its depletion causes an accumulation of TOP1–cc structures responsible for the high levels of intrinsic DNA damage. Thus, our data demonstrate that SCAT7 is an important constituent of the DNA damage response pathway and serves as a potential therapeutic target for hard-to-treat drug resistant cancers.

Sign in / Sign up

Export Citation Format

Share Document