scholarly journals DNA damage in embryonic neural stem cell determines FTLDs’ fate via early-stage neuronal necrosis

2021 ◽  
Vol 4 (7) ◽  
pp. e202101022
Author(s):  
Hidenori Homma ◽  
Hikari Tanaka ◽  
Meihua Jin ◽  
Xiaocen Jin ◽  
Yong Huang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Transcriptional Repression ◽  
Early Stage ◽  
Developmental Stress ◽  
Atypical Cell ◽  
Neuronal Necrosis ◽  
Damage Repair ◽  
Neural Stem Progenitor Cells ◽  
Cell Cycle Transition ◽  
Embryonic Neural Stem Cell

The early-stage pathologies of frontotemporal lobal degeneration (FTLD) remain largely unknown. In VCPT262A-KI mice carrying VCP gene mutation linked to FTLD, insufficient DNA damage repair in neural stem/progenitor cells (NSCs) activated DNA-PK and CDK1 that disabled MCM3 essential for the G1/S cell cycle transition. Abnormal neural exit produced neurons carrying over unrepaired DNA damage and induced early-stage transcriptional repression-induced atypical cell death (TRIAD) necrosis accompanied by the specific markers pSer46-MARCKS and YAP. In utero gene therapy expressing normal VCP or non-phosphorylated mutant MCM3 rescued DNA damage, neuronal necrosis, cognitive function, and TDP43 aggregation in adult neurons of VCPT262A-KI mice, whereas similar therapy in adulthood was less effective. The similar early-stage neuronal necrosis was detected in PGRNR504X-KI, CHMP2BQ165X-KI, and TDPN267S-KI mice, and blocked by embryonic treatment with AAV–non-phospho-MCM3. Moreover, YAP-dependent necrosis occurred in neurons of human FTLD patients, and consistently pSer46-MARCKS was increased in cerebrospinal fluid (CSF) and serum of these patients. Collectively, developmental stress followed by early-stage neuronal necrosis is a potential target for therapeutics and one of the earliest general biomarkers for FTLD.

scholarly journals HMGB1 signaling phosphorylates Ku70 and impairs DNA damage repair in Alzheimer’s disease pathology

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Hikari Tanaka ◽  
Kanoh Kondo ◽  
Kyota Fujita ◽  
Hidenori Homma ◽  
Kazuhiko Tagawa ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Damage ◽  
Cell Death ◽  
Transcriptional Repression ◽  
Dna Damage Repair ◽  
High Mobility ◽  
Hmgb1 Protein ◽  
Atypical Cell ◽  
Damage Repair

AbstractDNA damage is increased in Alzheimer’s disease (AD), while the underlying mechanisms are unknown. Here, we employ comprehensive phosphoproteome analysis, and identify abnormal phosphorylation of 70 kDa subunit of Ku antigen (Ku70) at Ser77/78, which prevents Ku70-DNA interaction, in human AD postmortem brains. The abnormal phosphorylation inhibits accumulation of Ku70 to the foci of DNA double strand break (DSB), impairs DNA damage repair and eventually causes transcriptional repression-induced atypical cell death (TRIAD). Cells under TRIAD necrosis reveal senescence phenotypes. Extracellular high mobility group box 1 (HMGB1) protein, which is released from necrotic or hyper-activated neurons in AD, binds to toll-like receptor 4 (TLR4) of neighboring neurons, and activates protein kinase C alpha (PKCα) that executes Ku70 phosphorylation at Ser77/78. Administration of human monoclonal anti-HMGB1 antibody to post-symptomatic AD model mice decreases neuronal DSBs, suppresses secondary TRIAD necrosis of neurons, prevents escalation of neurodegeneration, and ameliorates cognitive symptoms. TRIAD shares multiple features with senescence. These results discover the HMGB1-Ku70 axis that accounts for the increase of neuronal DNA damage and secondary enhancement of TRIAD, the cell death phenotype of senescence, in AD.

Genomic instability and DNA damage repair in clear cell renal cell carcinoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4581-4581
Author(s):  
Patrick Glen Pilie ◽  
Lijun Zhou ◽  
Pan Tong ◽  
Surena F. Matin ◽  
Kanishka Sircar ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Dna Damage ◽  
Cell Carcinoma ◽  
Genomic Instability ◽  
Renal Cell ◽  
Clear Cell ◽  
Early Stage ◽  
Cell Renal Cell Carcinoma ◽  
Mutator Phenotype ◽  
Damage Repair

4581 Background: Kidney cancer accounts for 2-3% of all new cancers with clear cell renal cell carcinoma (ccRCC) the most common subtype. ccRCC is characterized by a high level of genomic instability, suggesting defective DNA damage repair (DDR). The most frequent genomic alteration in ccRCC involves loss of the 3p chromosomal arm which harbors the von Hippel Lindau gene ( VHL), in addition to nearby genes SETD2, BAP1, and PBRM. We hypothesized that VHL loss leads to defective DDR as an early event in ccRCC carcinogenesis, giving way to a mutator phenotype. We posited that assessment of very early ccRCC tumors would inform us regarding the core mutations required to drive tumorigenesis in ccRCC, and that we could confirm these findings in appropriate model systems. Methods: We performed whole-exome (WES) DNA sequencing on 11 early-stage ccRCC tumors from 5 individuals, along with their matched normal DNA. We then analyzed ccRCC samples with and without somatic VHL mutations from the Cancer Genome Atlas (TCGA) for mutational load. Finally we assessed DDR signaling activity in renal proximal tubular cell lines (RPTEC) with VHL/SETD2 knockdown and in murine embryo fibroblasts (MEFs) from Vhl and Setd2knockout mice treated with etoposide via γH2AX expression and direct repeat-green fluorescent protein reporter assay. Results: All 11 samples revealed loss of 3p with pathogenic germline or somatic mutation in remaining VHL allele. No mutations were found in genes frequently mutated in larger ccRCC, including PBRM1, BAP1 or SETD2. WES revealed ~100 mutations/tumor, with no shared mutations across samples, even within the same individual. TCGA analysis showed similar mutational loads across ccRCC samples. MEFs with biallelic loss of Vhl and monoallelic loss of Setd2 and RPTEC with VHL and SETD2knockdown displayed increased DNA damage with impaired homologous repair and increased non-homologous end joining (NHEJ). Conclusions: Early stage ccRCC tumors with loss of VHL and chr 3p demonstrate genomic instability and a mutator phenotype similar to more advanced ccRCC. Cell line models of early ccRCC show increased DNA damage with a greater reliance on error-prone NHEJ machinery. These defects could be targeted for synthetic lethal treatment strategies.

Alterations of DNA damage repair genes in Chinese colorectal cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16121-e16121
Author(s):  
Wenliang Li ◽  
Zhu Zhu ◽  
Ning Xu ◽  
Wei Huang ◽  
Junping Shi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Excision Repair ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Dna Damage Repair ◽  
Molecular Characteristics ◽  
Damage Repair

e16121 Background: Colorectal cancer (CRC) is the second most common cancer in women and third in men. DNA damage repair (DDR) deficiency has emerged as a predictive biomarker for chemotherapy, PARP and immune checkpoint inhibitors. However, comprehensive molecular characteristics of DDR variants in Chinese CRC patients is lacking. Methods: Formalin fixed, paraffin embedded (FFPE) tumor tissues and matched blood samples were collected for targeted next-generation sequencing (NGS) assay. The testing was carried out in a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Alterations of six functional gene sets involved in DDR pathways: homologous recombination (HR), mismatch repair (MMR), base excision repair (BER), nonhomologous end-joining (NHEJ), checkpoint factors (CPF) and Fanconi anemia (FA) were analyzed. The association of DDR gene mutations with TMB/MSI was assessed. Results: In total, 319 CRC patients were recruited, 127 female and 192 male with a median age of 59 (range 23-92). Over one third (36%,115/319) patients had at least one mutation in DDR genes. Mutation rates varied in different DDR pathway: HR (20.7%), CPF (15.1%), FA (11.3%), MMR (10.3%), BER (8.8%), and NHEJ (5.3%). The most frequently mutated DDR genes were ARID1A (13.4%), ATM (10.2%), BRCA2 (6.8%), MLH1 (5.6%), MSH6 (5.6%), POLE (5.0%). Germline mutations in MLH1 (2.5%), BRCA2 (1.2%), MSH2 (0.9%), MSH6 (0.9%), FANCA (0.9%), ATM (0.6%), BRCA1 (0.3%), and CHEK2 (0.3%) were detected in 24 patients. DDR variations were enriched in the right-side CRC compared to the left side CRC (50% vs. 32.8%, p= 0.024). Early stage (I-II) harbored more DDR variations. 20.1% of patients had high TMB (≥10 muts/Mb) with a median of 51 muts/Mb (10-326.7 mus/Mb). Patients with DDR mutations had a significantly higher TMB than patients with wild type DDR (8.5 vs. 4.6 muts/Mb, p< 0.001). All CRC tumors with high MSI harbored DDR mutations. Importantly, the mutations in “HM” (HR/MMR), but not BER/CPF/NHEJ/FA mutations, were significantly correlated with high MSI ( p< 0.001). Conclusions: DDR gene alterations occurred in 36% of Chinese CRC patients and were enriched in right sided tumors. DDR pathway alterations are relatively frequent in CRC and consideration for biomarker-enriched clinical trials with PARP, immune checkpoint inhibitors, and novel combinations are warranted.

366-OR: TCF19 Promotes Functional Beta-Cell Mass and Proliferative Capacity by Regulating DNA Damage Repair Pathways

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 366-OR
Author(s):  
GRACE H. YANG ◽  
JEE YOUNG HAN ◽  
SUKANYA LODH ◽  
JOSEPH T. BLUMER ◽  
DANIELLE FONTAINE ◽  
...  
Keyword(s):  
Dna Damage ◽  
Beta Cell ◽  
Dna Damage Repair ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Proliferative Capacity ◽  
Damage Repair ◽  
Repair Pathways
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