A5082539286- CRISPR and Genetic Engineering
- Chromosomal and Genetic Variations
- DNA Repair Mechanisms
- Colorectal Cancer Treatments and Studies
- Cancer Genomics and Diagnostics
- Lung Cancer Treatments and Mutations
- Cancer-related molecular mechanisms research
- Cancer, Lipids, and Metabolism
- RNA and protein synthesis mechanisms
- Gastric Cancer Management and Outcomes
- Genetic factors in colorectal cancer
- Pancreatic and Hepatic Oncology Research
- Cancer Diagnosis and Treatment
- Cancer Treatment and Pharmacology
- Cancer, Hypoxia, and Metabolism
- RNA modifications and cancer
- Plant Virus Research Studies
- Inflammatory Biomarkers in Disease Prognosis
- Ubiquitin and proteasome pathways
- Fungal and yeast genetics research
- Prostate Cancer Treatment and Research
- Peptidase Inhibition and Analysis
- Epigenetics and DNA Methylation
- Histone Deacetylase Inhibitors Research
- BRCA gene mutations in cancer
Dana-Farber Cancer Institute
2022-2024
Harvard University
2022-2024
Centro Oncológico de Galicia
2011-2024
Broad Institute
2023-2024
Massachusetts Institute of Technology
2023-2024
Beckman Research Institute
2015-2023
City of Hope
2015-2023
Cancer Genetics (United States)
2018-2020
Bennington College
2018
University of Southern California
2013
Abstract The LINE-1 (L1) retrotransposon is an ancient genetic parasite that has written around one-third of the human genome through a ‘copy and paste’ mechanism catalysed by its multifunctional enzyme, open reading frame 2 protein (ORF2p) 1 . ORF2p reverse transcriptase (RT) endonuclease activities have been implicated in pathophysiology cancer 2,3 , autoimmunity 4,5 ageing 6,7 making potential therapeutic target. However, lack structural mechanistic knowledge hampered efforts to...
Retrotransposons are genomic DNA sequences that copy themselves to new locations via RNA intermediates; LINE-1 is the only active and autonomous retrotransposon in human genome. The mobility of largely repressed somatic tissues but derepressed many cancers, where retrotransposition correlated with p53 mutation number alteration (CNA). In cell lines, inducing expression can cause double-strand breaks (DSBs) replication stress. Reanalyzing multiomic data from breast, ovarian, endometrial,...
CRISPR/Cas9-based genome editing has revolutionized experimental molecular biology and entered the clinical world for targeted gene therapy. Identifying DNA modifications occurring at CRISPR/Cas9 target sites is critical to determine efficiency safety of tools. Here we show that insertions LINE-1 (L1) retrotransposons can occur frequently sites. Together with PolyA-seq an improved amplicon sequencing, characterize more than 2500 de novo L1 multiple in HEK293T, HeLa U2OS cells. These...
Abstract Long interspersed element 1 (LINE-1) open reading frame protein (ORF1p) expression is a common feature of many cancer types, including high-grade serous ovarian carcinoma (HGSOC). Here, we report that ORF1p not only expressed but also released by and primary tumor cells. Immuno-multiple reaction monitoring-mass spectrometry assays showed confidently detectable in conditioned media, ascites, patients’ plasma, implicating as potential biomarker. Interestingly, fallopian tube (FT)...
Chromosomal deletion rearrangements mediated by repetitive elements often involve repeats separated several kilobases and sequences that are divergent. While such likely induced DNA double-strand breaks (DSBs), it has been unclear how the proximity of DSBs relative to repeat affects frequency events. We generated a reporter assay in mouse cells for rearrangement involving 0.4 Mb. this repeat-mediated (RMD) with two DSBs: 5′ DSB is just downstream from first 3′ varying distances upstream...
Human deoxycytidine deaminase APOBEC3A (Apo3A) acts as an HIV-1 restriction factor in cells of myeloid lineage yet functions separately a potent mutator for genomic DNA. Apo3A activity and C motif deamination specificity exhibit striking dependence on pH that reflects these two distinct biological processes. Upon infection macrophages, induces the formation autophagosomes, requires autophagosomes replication, whereas inhibiting lysosomal fusion indicative late stage autophagy. Here we show...
Repeat-mediated deletions (RMDs) often involve repetitive elements (e.g., short interspersed elements) with sequence divergence that is separated by several kilobase pairs (kbps). We have examined RMDs induced DNA double-strand breaks (DSBs) under varying conditions of repeat (identical versus 1% and 3% divergent) DSB/repeat distance (16 bp-28.4 kbp). find the BLM helicase promotes long distances 28.4 kbp), which consistent a role in extensive DSB end resection, because resection nucleases...
Chromosomal double strand breaks (DSBs) can initiate several signaling events, such as ubiquitination, however the precise influence of on DSB repair outcomes remains poorly understood. With an RNA interference screen, we found that E3 ubiquitin ligase RNF8 suppresses a deletion rearrangement mediated by canonical non-homologous end joining (C-NHEJ). We also EJ without insertion/deletion mutations, which is hallmark C-NHEJ. Conversely, promotes alternative (ALT-EJ) events involving...
Progenitor cells capable of self-renewal and differentiation in the adult human pancreas are an under-explored resource for regenerative medicine. Using micro-manipulation three-dimensional colony assays we identify within exocrine that resemble progenitor cells. Exocrine tissues were dissociated into single plated a assay containing methylcellulose 5% Matrigel. A subpopulation ductal formed colonies differentiated ductal, acinar, endocrine lineage cells, expanded up to 300-fold with ROCK...
Women who carry pathogenic mutations in BRCA1 and BRCA2 have a lifetime risk of developing breast cancer up to 80%. However, estimates vary part due genetic modifiers. We investigated the association RAD52 S346X variant as modifier ovarian cancers mutation carriers from Consortium Investigators Modifiers BRCA1/2. The allele was associated with reduced [per-allele hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.56-0.86; P 0.0008] lesser extent (per-allele HR 0.78, CI 0.64-0.97,...
Abstract Background Triple-negative breast cancer (TNBC) is an aggressive subtype of with a high mortality rate due to lack therapeutic targets. Many TNBC cells are reliant on extracellular arginine for survival and express levels binding immunoglobin protein (BiP), marker metastasis endoplasmic reticulum (ER) stress response. Methods In this study, the effect shortage BiP expression in cell line MDA-MB-231 was evaluated. Two stable lines were generated cells: first expressed wild-type BiP,...
LINE-1 (L1) retrotransposition is widespread in many cancers, especially those with a high burden of chromosomal rearrangements. However, whether and to what degree L1 activity directly impacts genome integrity unclear. Here, we apply whole-genome sequencing experimental models expression comprehensively define the spectrum genomic changes caused by L1. We provide definitive evidence that frequently causes both local long-range rearrangements, small large segmental copy-number alterations,...
Numerous putative heat shock protein 90 (Hsp90)-interacting proteins, which could represent novel folding clients or co-chaperones, have been identified in recent years. Two separate high-throughput screens yeast uncovered genetic effects between Hsp90 and components of the ER membrane complex (EMC), is required for tolerance to unfolded response stress yeast. Herein, we provide first experimental evidence supporting that there a genuine interaction with EMC. We demonstrate interactions EMC2...
The increasing identification of driver oncogenic alterations and progress targeted therapies addresses the need comprehensive alternatives to standard molecular methods. translation into clinical practice next-generation sequencing (NGS) panels is actually challenged by compliance high quality standards for accreditation. Herein, we present analytical feasibility study a hybridization capture-based NGS panel (Action OncoKitDx) analysis somatic mutations, copy number variants (CNVs),...
Abstract Introduction: Approximately 50% of human cancers have somatic integrations long interspersed element-1 (LINE-1; also known as L1). L1 is a retrotransposon that copies itself through RNA and integrates into new genomic loci. Although sequences comprise approximately 17% the genome, only 100-150 loci retained ability to retrotranspose. These full-length, retrotransposition-competent L1s are typically repressed in cells, but there evidence their significant reactivation cancers....
277 Background: Patients with metastatic pancreatic cancer (mPC) have poor prognosis. Given the activity of both capecitabine and erlotinib in cancer, we hypothesized that combination use two drugs first-line therapy would improve clinical outcomes these patients. Methods: A prospective, single arm, open-label, phase II study. received 1,000mg/m 2 twice daily on days 1-14 3-week cycles combined 150 mg po for 18 weeks, until disease progression, unacceptable toxicity or withdrawal, a...
620 Background: Activating B-type Raf kinase (BRAF) mutations, mostly missense V600E, occur in approximately 8% to 12% of patients with metastatic colorectal cancer (mCRC). BRAF (V600E) mt is a strong predictor poor prognosis, distinct clinical and pathological features. However, it unknown whether this mutation predictive any treatment benefit real world setting. Methods: We conducted an observational, retrospective, multicentric study V600E-mt mCRC treated at nine university Spanish...