scholarly journals Targeting homologous recombination and telomerase in Barrett’s adenocarcinoma: impact on telomere maintenance, genomic instability and tumor growth

Oncogene ◽  
2013 ◽  
Vol 33 (12) ◽  
pp. 1495-1505 ◽  
Author(s):  
R Lu ◽  
J Pal ◽  
L Buon ◽  
P Nanjappa ◽  
J Shi ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Tumor Growth ◽  
Genomic Instability ◽  
Telomere Maintenance ◽  
Barrett’S Adenocarcinoma

scholarly journals Elevated APE1 Mediates Dysregulation of Homologous Recombination in Myeloma: Mechanisms and Translational Significance

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2074-2074 ◽  
Author(s):  
Subodh Kumar ◽  
Maria Gkotzamanidou ◽  
Jagannath Pal ◽  
Renquan Lu ◽  
Puru Nanjappa ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Genomic Instability ◽  
Small Molecule ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Small Molecule Inhibitor ◽  
Telomere Maintenance ◽  
Dna Breaks ◽  
Molecule Inhibitor ◽  
Rad51 Promoter

Abstract We have previously shown that elevated homologous recombination (HR) activity mediates genomic instability and progression in myeloma. Moreover, elevated HR also plays critical role in tumor growth by contributing to telomere maintenance and other survival mechanisms. We have now investigated molecular mechanisms driving dysregulated HR in MM. We observe that elevated apurinic apyrimidic endonuclease 1 (APE1) significantly contributes to dysregulation of HR, directly through transcriptional control of RAD51 as well as indirectly through its ability to induce DNA breaks. The transgenic suppression using APE1-specifc shRNA inhibits RAD51 expression, HR activity, and genomic instability as measured by SNP array profile in MM cells; whereas its induction leads to increased RAD51 expression, HR activity, genomic instability and oncogenic transformation in normal human cells. We have further investigated how APE1, a base excision repair protein, regulates RAD51, the key component of HR in myeloma and evaluated a novel small molecule inhibitor of APE1 for its impact on HR and associated genomic instability. Using an antibody array we observed that APE1 physically interacts with p73, a known transcriptional regulator of RAD51. To demonstrate that APE1 and P73 interact with RAD51 promoter in MM cells, we conducted chromatin immunoprecipitation (chip) assays and observed both P73 and APE1 binding to adjacent loci on RAD51 promoter. Taken together, these data suggest that elevated APE1 induces RAD51 expression through its interaction with P73. We next evaluated effect of a small molecule inhibitor specifically targeting nuclease function of APE1 in MM cells, and observed that it inhibits RAD51 expression, RAD51 foci, HR activity and reduces DNA breaks as assessed by g-H2AX levels on western blotting. The suppression of APE1 by this small molecule was associated with significant loss of RAD51 promoter activity, as assessed by a RAD51-promoter driven luciferase construct, as well as reduced RAD51 transcript levels. As APE1 is required for DNA repair which plays a critical part in development of drug resistance, we evaluated if APE1 inhibitor can help sensitize MM cells to DNA damaging agents. To investigate this we pretreated RPMI8226 and LR5 MM cells with the small molecule inhibitor of APE1 and then exposed them to various concentrations of melphalan for 48 hrs and cell viability and growth assessed. Pretreatment with APE1 inhibitor not only sensitized RPMI8226 cells to melphalan but also resistant LR5 cell line. These observations suggest that elevated APE1 is a critical target to induce DNA damage or overcome certain type of resistance possibly driven by repair mechanisms. In summary, we conclude that elevated APE1 is a critical intermediate for dysregulated HR and associated genomic instability, and small molecule inhibitor of APE1 has potential to reduce genomic instability, prevent/delay progression and improve clinical outcome in MM. Disclosures No relevant conflicts of interest to declare.

T1154 Role of Homologous Recombination in Telomere Maintenance and Evidence of ALT Pathway in Barrett's Adenocarcinoma Cells

2010 ◽  
Vol 138 (5) ◽  
pp. S-500
Author(s):  
Robert C. Bertheau ◽  
Jagannath Pal ◽  
Jason Y. Wong ◽  
Mariateresa Fulciniti ◽  
Ramesh B. Batchu ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Telomere Maintenance ◽  
Adenocarcinoma Cells ◽  
Barrett’S Adenocarcinoma

scholarly journals EXO1 Plays a Role in Generating Type I and Type II Survivors in Budding Yeast

Genetics ◽  
2004 ◽  
Vol 166 (4) ◽  
pp. 1641-1649
Author(s):  
Laura Maringele ◽  
David Lydall
Keyword(s):  
Homologous Recombination ◽  
Budding Yeast ◽  
Human Cells ◽  
Telomere Maintenance ◽  
Recombination Process ◽  
Yeast Cells ◽  
Type I ◽  
Type Ii ◽  
Recombination Proteins

Abstract Telomerase-defective budding yeast cells escape senescence by using homologous recombination to amplify telomeric or subtelomeric structures. Similarly, human cells that enter senescence can use homologous recombination for telomere maintenance, when telomerase cannot be activated. Although recombination proteins required to generate telomerase-independent survivors have been intensively studied, little is known about the nucleases that generate the substrates for recombination. Here we demonstrate that the Exo1 exonuclease is an initiator of the recombination process that allows cells to escape senescence and become immortal in the absence of telomerase. We show that EXO1 is important for generating type I survivors in yku70Δ mre11Δ cells and type II survivors in tlc1Δ cells. Moreover, in tlc1Δ cells, EXO1 seems to contribute to the senescence process itself.

Genomic profiling of biliary tract cancers to reveal clinically actionable genes and therapeutic biomarkers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16187-e16187
Author(s):  
Yang Shao ◽  
Qiuxiang Ou ◽  
Zhenhao Fang ◽  
Rui Liu ◽  
Hua Bao ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Genomic Instability ◽  
Biliary Tract ◽  
Large Scale ◽  
Excision Repair ◽  
State Transitions ◽  
Pathway Enrichment Analysis ◽  
Distal Cholangiocarcinoma ◽  
Tract Cancer

e16187 Background: Bile tract cancers are genetically and clinically heterogenous with a poor prognosis. Identifying novel biomarkers for targeted therapy is required to improve the clinical outcome of bile tract cancer patients. Methods: Tumor tissue samples of 482 Chinese biliary tract cancer (BTC) patients were genetically profiled using targeted next generation sequencing. Tumor mutation burden (TMB) was calculated by counting all nonsynonymous mutations per megabase of coding sequences. The R package ReactomePA was used in pathway enrichment analysis. Genomic instability was characterized by an in-house developed NGS-based Homologous Recombination Deficiency (HRD) panel and a HRD score was an unweighted sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST) scores. Results: The BTC cohort consisted of 135 gallbladder cancer (GBC), 73 intrahepatic cholangiocarcinoma (iCCA), 18 distal cholangiocarcinoma (dCCA), 14 perihilar cholangiocarcinoma (pCCA), while the remaining 242 BTC patients of no specific subtype information. Most frequently mutated genes included TP53 (56%), KRAS (25%), ARID1A (17%), SMAD4 (11%), and CDKN2A (10%) . A preliminary pathway analysis revealed that mutations of DNA damage repair (DDR) pathway genes were enriched in the cohort ( p< 1e-10), accounting for over 70% of the patients, particularly in homologous recombination repair (HRR), Fanconi anemia (FA), mismatch repair (MMR), and base excision repair (BER) genes. More specifically, approximately 50% of the cohort carried at least one mutation of the HRR genes (43%) or MMR genes (14%). Patients with impaired MMR had increased microsatellite instability status (MSI) comparing to those with wildtype MMR (33% vs. 3.1%, p< 0.0001), and patients harboring HRR mutations demonstrated elevated genomic instability than those without such mutations (median HRD: 18 vs.14, p < 0.05), indicative of potential response to poly (ADP-ribose) polymerase (PARP) inhibitors and other DNA-damage agents. Furthermore, high TMB was found to be highly correlated with DDR gene alterations ( p =0.004). In addition, we observed higher mutation frequencies of BRCA1/2 genes (including somatic and germline) in GBCs in contrast to other BTC subtypes. Conclusions: We herein reported the genomic features of 482 Chinese BTC samples and highlighted the role of DDR pathways including HRR and MMR. These findings could be useful to establish treatment and diagnostic strategies for BTC patients based on genetic information.

scholarly journals SIRT1 contributes to telomere maintenance and augments global homologous recombination

2010 ◽  
Vol 191 (7) ◽  
pp. 1299-1313 ◽  
Author(s):  
Jose A. Palacios ◽  
Daniel Herranz ◽  
Maria Luigia De Bonis ◽  
Susana Velasco ◽  
Manuel Serrano ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Telomerase Activity ◽  
Histone Deacetylation ◽  
Telomere Maintenance ◽  
Loss Of Function ◽  
Entire Genome ◽  
Telomere Shortening ◽  
Telomere Biology ◽  
Sir Complex

Yeast Sir2 deacetylase is a component of the silent information regulator (SIR) complex encompassing Sir2/Sir3/Sir4. Sir2 is recruited to telomeres through Rap1, and this complex spreads into subtelomeric DNA via histone deacetylation. However, potential functions at telomeres for SIRT1, the mammalian orthologue of yeast Sir2, are less clear. We studied both loss of function (SIRT1 deficient) and gain of function (SIRT1super) mouse models. Our results indicate that SIRT1 is a positive regulator of telomere length in vivo and attenuates telomere shortening associated with aging, an effect dependent on telomerase activity. Using chromatin immunoprecipitation assays, we find that SIRT1 interacts with telomeric repeats in vivo. In addition, SIRT1 overexpression increases homologous recombination throughout the entire genome, including telomeres, centromeres, and chromosome arms. These findings link SIRT1 to telomere biology and global DNA repair and provide new mechanistic explanations for the known functions of SIRT1 in protection from DNA damage and some age-associated pathologies.

scholarly journals Breast Cancer: A Molecularly Heterogenous Disease Needing Subtype-Specific Treatments

2020 ◽  
Vol 8 (1) ◽  
pp. 18 ◽  
Author(s):  
Ugo Testa ◽  
Germana Castelli ◽  
Elvira Pelosi
Keyword(s):  
Breast Cancer ◽  
Genomic Instability ◽  
Hormone Receptors ◽  
Early Stage ◽  
Brca Mutation ◽  
Clonal Evolution ◽  
Metastatic Breast ◽  
Genetic Alterations ◽  
Telomere Maintenance ◽  
Molecular Features

Breast cancer is the most commonly occurring cancer in women. There were over two-million new cases in world in 2018. It is the second leading cause of death from cancer in western countries. At the molecular level, breast cancer is a heterogeneous disease, which is characterized by high genomic instability evidenced by somatic gene mutations, copy number alterations, and chromosome structural rearrangements. The genomic instability is caused by defects in DNA damage repair, transcription, DNA replication, telomere maintenance and mitotic chromosome segregation. According to molecular features, breast cancers are subdivided in subtypes, according to activation of hormone receptors (estrogen receptor and progesterone receptor), of human epidermal growth factors receptor 2 (HER2), and or BRCA mutations. In-depth analyses of the molecular features of primary and metastatic breast cancer have shown the great heterogeneity of genetic alterations and their clonal evolution during disease development. These studies have contributed to identify a repertoire of numerous disease-causing genes that are altered through different mutational processes. While early-stage breast cancer is a curable disease in about 70% of patients, advanced breast cancer is largely incurable. However, molecular studies have contributed to develop new therapeutic approaches targeting HER2, CDK4/6, PI3K, or involving poly(ADP-ribose) polymerase inhibitors for BRCA mutation carriers and immunotherapy.

Bone Morphogenetic Protein-7 Inhibits Telomerase Activity, Telomere Maintenance, and Cervical Tumor Growth

2008 ◽  
Vol 68 (22) ◽  
pp. 9157-9166 ◽  
Author(s):  
Lucy Cassar ◽  
He Li ◽  
Alexander Ruvantha Pinto ◽  
Craig Nicholls ◽  
Sharyn Bayne ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Bone Morphogenetic Protein ◽  
Telomerase Activity ◽  
Telomere Maintenance ◽  
Cervical Tumor ◽  
Bone Morphogenetic Protein 7 ◽  
Morphogenetic Protein

scholarly journals Genetic Requirements for RAD51- andRAD54-Independent Break-Induced Replication Repair of a Chromosomal Double-Strand Break

2001 ◽  
Vol 21 (6) ◽  
pp. 2048-2056 ◽  
Author(s):  
Laurence Signon ◽  
Anna Malkova ◽  
Maria L. Naylor ◽  
Hannah Klein ◽  
James E. Haber
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Homologous Recombination ◽  
Gene Conversion ◽  
Strand Break ◽  
Double Strand Break ◽  
Telomere Maintenance ◽  
Diploid Cells ◽  
Break Induced Replication ◽  
In Cells

ABSTRACT Broken chromosomes can be repaired by several homologous recombination mechanisms, including gene conversion and break-induced replication (BIR). In Saccharomyces cerevisiae, an HO endonuclease-induced double-strand break (DSB) is normally repaired by gene conversion. Previously, we have shown that in the absence ofRAD52, repair is nearly absent and diploid cells lose the broken chromosome; however, in cells lacking RAD51, gene conversion is absent but cells can repair the DSB by BIR. We now report that gene conversion is also abolished when RAD54, RAD55, and RAD57 are deleted but BIR occurs, as withrad51Δ cells. DSB-induced gene conversion is not significantly affected when RAD50, RAD59, TID1(RDH54), SRS2, or SGS1 is deleted. Various double mutations largely eliminate both gene conversion and BIR, including rad51Δ rad50Δ, rad51Δ rad59Δ, andrad54Δ tid1Δ. These results demonstrate that there is aRAD51- and RAD54-independent BIR pathway that requires RAD59, TID1, RAD50, and presumablyMRE11 and XRS2. The similar genetic requirements for BIR and telomere maintenance in the absence of telomerase also suggest that these two processes proceed by similar mechanisms.

scholarly journals Long Palindromic Sequences Induce Double-Strand Breaks during Meiosis in Yeast

2000 ◽  
Vol 20 (10) ◽  
pp. 3449-3458 ◽  
Author(s):  
Farooq Nasar ◽  
Craig Jankowski ◽  
Dilip K. Nag
Keyword(s):  
Homologous Recombination ◽  
Genomic Instability ◽  
Double Strand Breaks ◽  
Gene Products ◽  
Strand Breaks ◽  
Hairpin Formation ◽  
Palindromic Sequences ◽  
Normal Meiosis ◽  
Eukaryotic Genomes

ABSTRACT Inverted-repeated or palindromic sequences have been found to occur in both prokaryotic and eukaryotic genomes. Such repeated sequences are usually short and present at several functionally important regions in the genome. However, long palindromic sequences are rare and are a major source of genomic instability. The palindrome-mediated genomic instability is believed to be due to cruciform or hairpin formation and subsequent cleavage of this structure by structure-specific nucleases. Here we present both genetic and physical evidence that long palindromic sequences (>50 bp) generate double-strand breaks (DSBs) at a high frequency during meiosis in the yeast Saccharomyces cerevisiae. The palindrome-mediated DSB formation depends on the primary sequence of the inverted repeat and the location and length of the repeated units. The DSB formation at the palindrome requires all of the gene products that are known to be responsible for DSB formation at the normal meiosis-specific sites. Since DSBs are initiators of nearly all meiotic recombination events, most of the palindrome-induced breaks appear to be repaired by homologous recombination. Our results suggest that short palindromic sequences are highly stable in vivo. In contrast, long palindromic sequences make the genome unstable by inducing DSBs and such sequences are usually removed from the genome by homologous recombination events.

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