Balca R Mardin

Balca R Mardin
BioMedX · DNA Damage in Cancer

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48
Publications
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1,468
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Publications

Publications (48)
Preprint
Full-text available
Patients with chronic obstructive pulmonary disease (COPD) are still waiting for curative treatments. Considering the environmental cause of COPD (e.g., cigarette smoke) and disease phenotypes, including stem-cell senescence and impaired differentiation, we hypothesized that COPD will be associated with altered epigenetic signaling in lung cells. W...
Article
The occurrence and formation of genomic structural variants (SV) is known to be influenced by the 3D chromatin architecture, but the extent and magnitude have been challenging to study. Here, we apply Hi-C to study chromatin organization before and after induction of chromothripsis in human cells. We use Hi-C to manually assemble the derivative chr...
Article
Full-text available
Chromosome loss that results in monosomy is detrimental to viability, yet it is frequently observed in cancers. How cancers survive with monosomy is unknown. Using p53-deficient monosomic cell lines, we find that chromosome loss impairs proliferation and genomic stability. Transcriptome and proteome analysis demonstrates reduced expression of genes...
Article
Full-text available
Background Synthetic lethality describes a genetic interaction between two perturbations, leading to cell death, whereas neither event alone has a significant effect on cell viability. This concept can be exploited to specifically target tumor cells. CRISPR viability screens have been widely employed to identify cancer vulnerabilities. However, an...
Preprint
Full-text available
The occurrence and formation of genomic structural variants (SV) is known to be influenced by the 3D chromatin architecture , but the extent and magnitude has been challenging to study. Here, we apply Hi-C to study chromatin organization before and after induction of chromothripsis in human cells. We use Hi-C to manually assemble the derivative chr...
Preprint
Full-text available
Chromosome loss that results in monosomy is detrimental to viability, yet, it is frequently observed in cancers. How cancers survive with monosomy is unknown. Using p53 deficient monosomic cell lines, we found that chromosome loss impairs proliferation and genomic stability. Transcriptome and proteome analysis revealed a partial compensation of the...
Article
Full-text available
Double-strand breaks (DSBs) are the most toxic type of DNA lesions. Cells repair these lesions using either end protection- or end resection-coupled mechanisms. To study DSB repair choice, we present the Color Assay Tracing-Repair (CAT-R) to simultaneously quantify DSB repair via end protection and end resection pathways. CAT-R introduces DSBs usin...
Article
Full-text available
TP53 deficiency is the most common alteration in cancer; however, this alone is typically insufficient to drive tumorigenesis. To identify genes promoting tumorigenesis in combination with TP53 deficiency, we perform genome-wide CRISPR-Cas9 knockout screens coupled with proliferation and transformation assays in isogenic cell lines. Loss of several...
Article
Full-text available
Structural variation (SV), involving deletions, duplications, inversions and translocations of DNA segments, is a major source of genetic variability in somatic cells and can dysregulate cancer-related pathways. However, discovering somatic SVs in single cells has been challenging, with copy-number-neutral and complex variants typically escaping de...
Article
Full-text available
Abstract Arrayed CRISPR‐based screens emerge as a powerful alternative to pooled screens making it possible to investigate a wide range of cellular phenotypes that are typically not amenable to pooled screens. Here, we describe a solid‐phase transfection platform that enables CRISPR‐based genetic screens in arrayed format with flexible readouts. We...
Preprint
Full-text available
Structural variation (SV), where rearrangements delete, duplicate, invert or translocate DNA segments, is a major source of somatic cell variation. It can arise in rapid bursts, mediate genetic heterogeneity, and dysregulate cancer-related pathways. The challenge to systematically discover SVs in single cells remains unsolved, with copy-neutral and...
Poster
Full-text available
DNA double stranded breaks (DSBs) are one of the most deleterious types of DNA lesions. Mammalian cells have multiple pathways for repairing such lesions, including non-homologous end-joining (NHEJ), homologous recombination (HR), single-strand annealing (SSA) and alternative end-joining (alt-EJ). Despite the immense amount of work on the function...
Article
Background: Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for futur...
Poster
Full-text available
DNA double stranded breaks (DSBs) are one of the most deleterious types of DNA lesions. Mammalian cells have multiple pathways for repairing such lesions, including non-homologous end-joining (NHEJ), homologous recombination (HR), single-strand annealing (SSA) and alternative end-joining (alt-EJ). In spite of the immense amount of work on the func...
Article
Full-text available
To ensure genomic integrity, living organisms have evolved diverse molecular processes for sensing and repairing damaged DNA. If improperly repaired, DNA damage can give rise to different types of mutations, an important class of which are the genomic structural variants (SVs). In spite of their importance for phenotypic variation and genome evolut...
Article
A small fraction of all cells within individual tumours from colorectal cancer (CRC) patients drives long term tumor growth and metastases in immune-compromised mice. Targeting these tumor-initiating cells (TIC) may improve the long-term outcome in advanced CRC. To identify candidate genes which drive proliferation and survival of TIC, we have perf...
Article
Full-text available
Patterns of gene expression in tumors can arise as a consequence of or result in genomic instability, characterized by the accumulation of somatic copy number alterations (SCNAs) and point mutations (PMs). Expression signatures have been widely used as markers for genomic instability, and both SCNAs and PMs could be thought to associate with distin...
Article
Full-text available
Extensive prior research focused on somatic copy-number alterations (SCNAs) affecting cancer genes, yet the extent to which recurrent SCNAs exert their influence through rearrangement of cis-regulatory elements (CREs) remains unclear. Here we present a framework for inferring cancer-related gene overexpression resulting from CRE reorganization (e.g...
Data
Movie S3. Micronucleus Formation in KrasG12D/Mad2-Positive Spheroid Culture, Related to Figure 4 Time-lapse imaging of a KrasG12D/Mad2-positive acinus showing a mitotic cell (red circle) that divides and forms a micronucleus, t = 0 after 30 hr on doxycycline; H2B-GFP (green).
Data
Movie S4. Chromosome Misalignment in KrasG12D/Mad2-Positive Spheroid Culture, Related to Figure 4 Time-lapse imaging of KrasG12D/Mad2 positive acinus with a mitotic cell (red circle) undergoing apoptosis after severe chromosome misalignments, t = 0 after 30 hr on doxycycline; H2B-GFP (green).
Data
Movie S2. Cell Division in KrasG12D-Positive Spheroid Culture, Related to Figure 4 Time-lapse imaging of cell (red circle) entering mitosis and completing cell division inside the epithelial rim in a KrasG12D-positive spheroid in vitro, t = 0 after 30 hr on doxycycline; H2B-GFP (green).
Data
Time-lapse imaging of a cell division (red circle) in a control culture oriented perpendicular to the apical and basal membrane within the epithelial layer; H2B-GFP (green).
Data
Movie S5. Cytokinesis Failure in KrasG12D/Mad2-Positive Spheroid Culture, Related to Figure 4 Time-lapse imaging of KrasG12D/Mad2-positive spheroid with a mitotic cell (red circle) failing to complete nuclear division, t = 0 after 30 hr on doxycycline; H2B-GFP (green).
Article
Full-text available
Chromosome instability (CIN) is associated with poor survival and therapeutic outcome in a number of malignancies. Despite this correlation, CIN can also lead to growth disadvantages. Here, we show that simultaneous overexpression of the mitotic checkpoint protein Mad2 with KrasG12D or Her2 in mammary glands of adult mice results in mitotic checkpo...
Article
Characterizing genomic structural variations (SVs) in the human genome remains challenging, and there is a growing interest to understand somatic SVs occurring in cancer, a disease of the genome. A havoc-causing SV process known as chromothripsis scars the genome when localized chromosome shattering and repair occur in a one-off catastrophe. Recent...
Article
Congenital gliobastoma multiforme (GBM) is rare and little is known about the molecular defects underlying the initiation and progression of this tumor type. We present a case of congenital GBM analyzed by conventional cytogenetics, fluorescence in situ hybridization, array comparative genomic hybridization and next generation sequencing. On cytoge...
Article
High-risk human papillomavirus (hrHPV) types induce immortalization of primary human epithelial cells. Previously we demonstrated that immortalization of human foreskin keratinocytes (HFKs) is HPV type dependent, as reflected by the presence or absence of a crisis period before reaching immortality. This study determined how the immortalization cap...
Article
Full-text available
A remarkable observation emerging from recent cancer genome analyses is the identification of chromothripsis as a one-off genomic catastrophe, resulting in massive somatic DNA structural rearrangements (SRs). Largely due to lack of suitable model systems, the mechanistic basis of chromothripsis has remained elusive. We developed an integrative meth...
Article
The centrosome is the main microtubule (MT)-organizing centre of animal cells. It consists of two centrioles and a multi-layered proteinaceous structure that surrounds the centrioles, the so-called pericentriolar material. Centrosomes promote de novo assembly of MTs and thus play important roles in Golgi organization, cell polarity, cell motility a...
Article
Timely and accurate assembly of the mitotic spindle is critical for the faithful segregation of chromosomes, and centrosome separation is a key step in this process. The timing of centrosome separation varies dramatically between cell types; however, the mechanisms responsible for these differences and its significance are unclear. Here, we show th...
Article
Full-text available
The functional state of a cell is largely determined by the spatiotemporal organization of its proteome. Technologies exist for measuring particular aspects of protein turnover and localization, but comprehensive analysis of protein dynamics across different scales is possible only by combining several methods. Here we describe tandem fluorescent p...
Article
Full-text available
The centrosome, which consists of two centrioles and the surrounding pericentriolar material, is the primary microtubule-organizing center (MTOC) in animal cells. Like chromosomes, centrosomes duplicate once per cell cycle and defects that lead to abnormalities in the number of centrosomes result in genomic instability, a hallmark of most cancer ce...
Article
In human cells, separation of the centrosomes and formation of a bipolar spindle are essential for correct chromosome segregation [1]. During interphase, centrosomes are joined together by the linker proteins C-Nap1 and rootletin [2-4]. At the onset of mitosis, these linker proteins are phosphorylated and displaced from centrosomes by the Nek2A kin...
Article
Full-text available
During interphase, centrosomes are held together by a proteinaceous linker that connects the proximal ends of the mother and daughter centriole. This linker is disassembled at the onset of mitosis in a process known as centrosome disjunction, thereby facilitating centrosome separation and bipolar spindle formation. The NIMA (never in mitosis A)-rel...

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Project
DNA double stranded breaks (DSBs) are one of the most deleterious types of DNA lesions. Mammalian cells have multiple pathways for repairing such lesions, including non-homologous end-joining (NHEJ), homologous recombination (HR), single-strand annealing (SSA) and alternative end-joining (alt-EJ). Despite the immense amount of work on the function of individual molecules, the interplay between the DSB repair pathways are less studied. To study the DNA DSB repair choices in vitro we developed and employed Colour Assay Tracing Repair (CAT-R) as a fluorescent reporter system.