scholarly journals Aneuploidy and a deregulated DNA damage response suggest haploinsufficiency in breast tissues of BRCA2 mutation carriers

2020 ◽  
Vol 6 (5) ◽  
pp. eaay2611 ◽  
Author(s):  
Mihriban Karaayvaz-Yildirim ◽  
Rebecca E. Silberman ◽  
Adam Langenbucher ◽  
Srinivas Vinod Saladi ◽  
Kenneth N. Ross ◽  
...  
Keyword(s):  
Dna Damage ◽  
Brca2 Mutation ◽  
Copy Number Variations ◽  
Replication Checkpoint ◽  
Mutation Carriers ◽  
Damage Response ◽  
Risk Patients ◽  
Breast Tissues ◽  
Lp Cells

Women harboring heterozygous germline mutations of BRCA2 have a 50 to 80% risk of developing breast cancer, yet the pathogenesis of these cancers is poorly understood. To reveal early steps in BRCA2-associated carcinogenesis, we analyzed sorted cell populations from freshly-isolated, non-cancerous breast tissues of BRCA2 mutation carriers and matched controls. Single-cell whole-genome sequencing demonstrates that >25% of BRCA2 carrier (BRCA2mut/+) luminal progenitor (LP) cells exhibit sub-chromosomal copy number variations, which are rarely observed in non-carriers. Correspondingly, primary BRCA2mut/+ breast epithelia exhibit DNA damage together with attenuated replication checkpoint and apoptotic responses, and an age-associated expansion of the LP compartment. We provide evidence that these phenotypes do not require loss of the wild-type BRCA2 allele. Collectively, our findings suggest that BRCA2 haploinsufficiency and associated DNA damage precede histologic abnormalities in vivo. Using these hallmarks of cancer predisposition will yield unanticipated opportunities for improved risk assessment and prevention strategies in high-risk patients.

scholarly journals Aneuploidy and deregulated DNA damage response define haploinsufficiency in breast tissues of BRCA2 mutation carriers

2019 ◽  
Author(s):  
Mihriban Karaayvaz ◽  
Rebecca E Silberman ◽  
Adam Langenbucher ◽  
Srinivas Vinod Saladi ◽  
Kenneth N Ross ◽  
...  
Keyword(s):  
Dna Damage ◽  
Brca2 Mutation ◽  
Copy Number Variations ◽  
Cancer Risk Assessment ◽  
Replication Checkpoint ◽  
Mutation Carriers ◽  
Risk Patients ◽  
Breast Tissues ◽  
Lp Cells

AbstractWomen harboring heterozygous germline mutations of BRCA2 have a 50-80% risk of developing breast cancer, yet the early pathogenesis of these cancers is poorly understood. We sought to reveal early steps in BRCA2-associated carcinogenesis through analysis of sorted cell populations from freshly-isolated, non-cancerous breast tissues among a cohort of BRCA2 mutation carriers and matched controls. Single-cell whole-genome sequencing demonstrates that >25% of BRCA2 carrier (BRCA2mut/+) luminal progenitor (LP) cells exhibit sub-chromosomal copy number variations (CNVs), which are rarely observed in non-carriers. Correspondingly, primary BRCA2mut/+ breast epithelia exhibit spontaneous and replication stress-induced DNA damage together with attenuated replication checkpoint and apoptotic responses, associated with an age-associated expansion of the LP compartment in human carrier tissues. These phenotypes are not associated with loss of wild-type BRCA2. Collectively, these findings provide evidence for BRCA2 haploinsufficiency and associated DNA damage in vivo that precede histologic abnormalities. These results provide unanticipated opportunities for new cancer risk assessment and prevention strategies in high-risk patients.

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.

scholarly journals PAICS contributes to gastric carcinogenesis and participates in DNA damage response by interacting with histone deacetylase 1/2

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Nan Huang ◽  
Chang Xu ◽  
Liang Deng ◽  
Xue Li ◽  
Zhixuan Bian ◽  
...  
Keyword(s):  
Dna Damage ◽  
Histone Deacetylase ◽  
Dna Damage Response ◽  
De Novo ◽  
Dna Damage Repair ◽  
Histone Deacetylase 1 ◽  
Damage Repair ◽  
Damage Response

AbstractPhosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), an essential enzyme involved in de novo purine biosynthesis, is connected with formation of various tumors. However, the specific biological roles and related mechanisms of PAICS in gastric cancer (GC) remain unclear. In the present study, we identified for the first time that PAICS was significantly upregulated in GC and high expression of PAICS was correlated with poor prognosis of patients with GC. In addition, knockdown of PAICS significantly induced cell apoptosis, and inhibited GC cell growth both in vitro and in vivo. Mechanistic studies first found that PAICS was engaged in DNA damage response, and knockdown of PAICS in GC cell lines induced DNA damage and impaired DNA damage repair efficiency. Further explorations revealed that PAICS interacted with histone deacetylase HDAC1 and HDAC2, and PAICS deficiency decreased the expression of DAD51 and inhibited its recruitment to DNA damage sites by impairing HDAC1/2 deacetylase activity, eventually preventing DNA damage repair. Consistently, PAICS deficiency enhanced the sensitivity of GC cells to DNA damage agent, cisplatin (CDDP), both in vitro and in vivo. Altogether, our findings demonstrate that PAICS plays an oncogenic role in GC, which act as a novel diagnosis and prognostic biomarker for patients with GC.

scholarly journals Slx4 Regulates DNA Damage Checkpoint-dependent Phosphorylation of the BRCT Domain Protein Rtt107/Esc4

2006 ◽  
Vol 17 (1) ◽  
pp. 539-548 ◽  
Author(s):  
Tania M. Roberts ◽  
Michael S. Kobor ◽  
Suzanne A. Bastin-Shanower ◽  
Miki Ii ◽  
Sonja A. Horte ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Dna Damage Checkpoint ◽  
Checkpoint Activation ◽  
Alkylation Damage ◽  
Binding Partner ◽  
Replication Restart ◽  
Damage Response ◽  
Domain Protein

RTT107 (ESC4, YHR154W) encodes a BRCA1 C-terminal-domain protein that is important for recovery from DNA damage during S phase. Rtt107 is a substrate of the checkpoint protein kinase Mec1, although the mechanism by which Rtt107 is targeted by Mec1 after checkpoint activation is currently unclear. Slx4, a component of the Slx1-Slx4 structure-specific nuclease, formed a complex with Rtt107. Deletion of SLX4 conferred many of the same DNA-repair defects observed in rtt107Δ, including DNA damage sensitivity, prolonged DNA damage checkpoint activation, and increased spontaneous DNA damage. These phenotypes were not shared by the Slx4 binding partner Slx1, suggesting that the functions of the Slx4 and Slx1 proteins in the DNA damage response were not identical. Of particular interest, Slx4, but not Slx1, was required for phosphorylation of Rtt107 by Mec1 in vivo, indicating that Slx4 was a mediator of DNA damage-dependent phosphorylation of the checkpoint effector Rtt107. We propose that Slx4 has roles in the DNA damage response that are distinct from the function of Slx1-Slx4 in maintaining rDNA structure and that Slx4-dependent phosphorylation of Rtt107 by Mec1 is critical for replication restart after alkylation damage.

scholarly journals Dephosphorylation of the C-terminal Tyrosyl Residue of the DNA Damage-related Histone H2A.X Is Mediated by the Protein Phosphatase Eyes Absent

2009 ◽  
Vol 284 (24) ◽  
pp. 16066-16070 ◽  
Author(s):  
Navasona Krishnan ◽  
Dae Gwin Jeong ◽  
Suk-Kyeong Jung ◽  
Seong Eon Ryu ◽  
Andrew Xiao ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Mammalian Cells ◽  
Protein Tyrosine Phosphatases ◽  
Histone H2a ◽  
Eyes Absent ◽  
Damage Repair ◽  
Damage Response

In mammalian cells, the DNA damage-related histone H2A variant H2A.X is characterized by a C-terminal tyrosyl residue, Tyr-142, which is phosphorylated by an atypical kinase, WSTF. The phosphorylation status of Tyr-142 in H2A.X has been shown to be an important regulator of the DNA damage response by controlling the formation of γH2A.X foci, which are platforms for recruiting molecules involved in DNA damage repair and signaling. In this work, we present evidence to support the identification of the Eyes Absent (EYA) phosphatases, protein-tyrosine phosphatases of the haloacid dehalogenase superfamily, as being responsible for dephosphorylating the C-terminal tyrosyl residue of histone H2A.X. We demonstrate that EYA2 and EYA3 displayed specificity for Tyr-142 of H2A.X in assays in vitro. Suppression of eya3 by RNA interference resulted in elevated basal phosphorylation and inhibited DNA damage-induced dephosphorylation of Tyr-142 of H2A.X in vivo. This study provides the first indication of a physiological substrate for the EYA phosphatases and suggests a novel role for these enzymes in regulation of the DNA damage response.

scholarly journals SIRT7-mediated ATM deacetylation is essential for its deactivation and DNA damage repair

2019 ◽  
Vol 5 (3) ◽  
pp. eaav1118 ◽  
Author(s):  
Ming Tang ◽  
Zhiming Li ◽  
Chaohua Zhang ◽  
Xiaopeng Lu ◽  
Bo Tu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Class Iii ◽  
Ataxia Telangiectasia Mutated ◽  
Damage Repair ◽  
Damage Response ◽  
Late Stages

The activation of ataxia-telangiectasia mutated (ATM) upon DNA damage involves a cascade of reactions, including acetylation by TIP60 and autophosphorylation. However, how ATM is progressively deactivated after completing DNA damage repair remains obscure. Here, we report that sirtuin 7 (SIRT7)–mediated deacetylation is essential for dephosphorylation and deactivation of ATM. We show that SIRT7, a class III histone deacetylase, interacts with and deacetylates ATM in vitro and in vivo. In response to DNA damage, SIRT7 is mobilized onto chromatin and deacetylates ATM during the late stages of DNA damage response, when ATM is being gradually deactivated. Deacetylation of ATM by SIRT7 is prerequisite for its dephosphorylation by its phosphatase WIP1. Consequently, depletion of SIRT7 or acetylation-mimic mutation of ATM induces persistent ATM phosphorylation and activation, thus leading to impaired DNA damage repair. Together, our findings reveal a previously unidentified role of SIRT7 in regulating ATM activity and DNA damage repair.

scholarly journals The Circadian Gene Period2 Plays an Important Role in Tumor Suppression and DNA-Damage Response In Vivo

Cell ◽  
2002 ◽  
Vol 111 (7) ◽  
pp. 1055 ◽  
Author(s):  
Loning Fu ◽  
Helene Pelicano ◽  
Jinsong Liu ◽  
Peng Huang ◽  
Cheng Chi Lee
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Tumor Suppression ◽  
Circadian Gene ◽  
Damage Response

scholarly journals Pie1, a Protein Interacting with Mec1, Controls Cell Growth and Checkpoint Responses in Saccharomyces cerevisiae

2001 ◽  
Vol 21 (3) ◽  
pp. 755-764 ◽  
Author(s):  
Tatsushi Wakayama ◽  
Tae Kondo ◽  
Seiko Ando ◽  
Kunihiro Matsumoto ◽  
Katsunori Sugimoto
Keyword(s):  
Dna Damage ◽  
Cell Growth ◽  
Kinase Activity ◽  
Critical Role ◽  
Kinase Domain ◽  
Protein Kinase Activity ◽  
Replication Checkpoint ◽  
Family Protein ◽  
Replication Block

ABSTRACT In eukaryotes, the ATM and ATR family proteins play a critical role in the DNA damage and replication checkpoint controls. These proteins are characterized by a kinase domain related to the phosphatidylinositol 3-kinase, but they have the ability to phosphorylate proteins. In budding yeast, the ATR family protein Mec1/Esr1 is essential for checkpoint responses and cell growth. We have isolated the PIE1 gene in a two-hybrid screen for proteins that interact with Mec1, and we show that Pie1 interacts physically with Mec1 in vivo. Like MEC1, PIE1is essential for cell growth, and deletion of the PIE1 gene causes defects in the DNA damage and replication block checkpoints similar to those observed in mec1Δ mutants. Rad53 hyperphosphorylation following DNA damage and replication block is also decreased in pie1Δ cells, as in mec1Δcells. Pie1 has a limited homology to fission yeast Rad26, which forms a complex with the ATR family protein Rad3. Mutation of the region in Pie1 homologous to Rad26 results in a phenotype similar to that of thepie1Δ mutation. Mec1 protein kinase activity appears to be essential for checkpoint responses and cell growth. However, Mec1 kinase activity is unaffected by the pie1Δ mutation, suggesting that Pie1 regulates some essential function other than Mec1 kinase activity. Thus, Pie1 is structurally and functionally related to Rad26 and interacts with Mec1 to control checkpoints and cell proliferation.

scholarly journals TIN2-Tethered TPP1 Recruits Human Telomerase to Telomeres In Vivo

2010 ◽  
Vol 30 (12) ◽  
pp. 2971-2982 ◽  
Author(s):  
Eladio Abreu ◽  
Elena Aritonovska ◽  
Patrick Reichenbach ◽  
Gaël Cristofari ◽  
Brad Culp ◽  
...  
Keyword(s):  
Dna Damage ◽  
Chromatin Immunoprecipitation ◽  
Shelterin Complex ◽  
Damage Response ◽  
Single Stranded Region ◽  
Ob Fold ◽  
Per Se ◽  
Human Telomerase

ABSTRACT Recruitment to telomeres is a pivotal step in the function and regulation of human telomerase; however, the molecular basis for recruitment is not known. Here, we have directly investigated the process of telomerase recruitment via fluorescence in situ hybridization (FISH) and chromatin immunoprecipitation (ChIP). We find that depletion of two components of the shelterin complex that is found at telomeres—TPP1 and the protein that tethers TPP1 to the complex, TIN2—results in a loss of telomerase recruitment. On the other hand, we find that the majority of the observed telomerase association with telomeres does not require POT1, the shelterin protein that links TPP1 to the single-stranded region of the telomere. Deletion of the oligonucleotide/oligosaccharide binding fold (OB-fold) of TPP1 disrupts telomerase recruitment. In addition, while loss of TPP1 results in the appearance of DNA damage factors at telomeres, the DNA damage response per se does not account for the telomerase recruitment defect observed in the absence of TPP1. Our findings indicate that TIN2-anchored TPP1 plays a major role in the recruitment of telomerase to telomeres in human cells and that recruitment does not depend on POT1 or interaction of the shelterin complex with the single-stranded region of the telomere.

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