Biology subjects

Bronder, D.

Publications and source records attributed to Bronder, D..

3 recordsLinked to original sources

bioRxiv2022

Mitotic clustering of pulverized chromosomes from micronuclei

Complex genome rearrangements can be generated by the catastrophic shattering of mis-segregated chromosomes trapped within micronuclei through a process known as chromothripsis. Since each chromosome harbors a single centromere, how acentric fragments derived from shattered chromosomes are inherited between daughter cells during mitosis remains unknown. Here we tracked micronucleated chromosomes by live-cell imaging and show that acentric fragments cluster in close spatial proximity throughout mitosis for biased partitioning to a single daughter cell. Mechanistically, the CIP2A-TOPB1 complex prematurely associates with DNA lesions within ruptured micronuclei during interphase, which poises chromosome fragments for clustering upon mitotic entry. Inactivation of CIP2A or TOPBP1 caused pulverized chromosomes to untether and disperse throughout the mitotic cell, consequently resulting in the mis-accumulation of DNA fragments in the cytoplasm. The inheritance of shattered chromosomes by a single daughter cell suggests that micronucleation can drive complex rearrangements that lack the DNA copy number oscillations characteristic of canonical chromothripsis. Comprehensive analysis of pan-cancer whole-genome sequencing data revealed clusters of DNA copy number-neutral rearrangements - termed balanced chromothripsis - across diverse cancer types resulting in the acquisition of known driver events. Thus, distinct patterns of chromothripsis can be explained by the spatial mitotic clustering of pulverized chromosomes from micronuclei.

cell biology↗

bioRxiv2021

TP53 loss initiates chromosomal instability in high-grade serous ovarian cancer

High-grade serous ovarian cancer (HGSOC) originates in the fallopian tube epithelium and is characterized by ubiquitous TP53 mutation and extensive chromosomal instability (CIN). While the direct causes of CIN are errors during DNA replication and/or chromosome segregation, mutations in genes encoding DNA replication and mitotic factors are rare in HGSOC. Thus, the drivers of CIN remain undefined. We therefore asked whether the oncogenic lesions that are frequently observed in HGSOC are capable of driving CIN via indirect mechanisms. To address this question, we genetically manipulated non-transformed hTERT-immortalized human fallopian tube epithelial cells to model homologous recombination deficiency (HRD) and oncogenic signalling in HGSOC. Using CRISPR/Cas9-mediated gene editing, we sequentially mutagenized the tumour suppressors TP53 and BRCA1, followed by overexpression of the MYC oncogene. Single-cell shallow-depth whole-genome sequencing revealed that loss of p53 function was sufficient to lead to the emergence of heterogenous karyotypes harbouring whole chromosome and chromosome arm aneuploidies, a phenomenon exacerbated by subsequent loss of BRCA1 function. In addition, whole-genome doubling events were observed in independent p53/BRCA1-deficient subclones. Global transcriptomics showed that TP53 mutation was also sufficient to deregulate gene expression modules involved in cell cycle commitment, DNA replication, G2/M checkpoint control and mitotic spindle function, suggesting that p53-deficiency induces cell cycle distortions that could precipitate CIN. Again, loss of BRCA1 function and MYC overexpression exacerbated these patterns of transcriptional deregulation. Thus, our observations support a model whereby the initial loss of the key tumour suppressor TP53 is sufficient to deregulate gene expression networks governing multiple cell cycle controls, and that this in turn is sufficient to drive CIN in pre-malignant fallopian tube epithelial cells. SUMMARY STATEMENTHigh-grade serous ovarian cancer is defined by TP53 mutation and chromosomal instability, the cause of which remains poorly understood. We developed a novel model system that implicates cell cycle deregulation upon p53-loss as cause of CIN.

cancer biology↗

bioRxiv2019

Cancer-type specific aneuploidies hard-wire chromosome-wide gene expression patterns of their tissue of origin

Most carcinomas have characteristic chromosomal aneuploidies specific to the tissue of tumor origin. The reason for this specificity is unknown. As aneuploidies directly affect gene expression, we hypothesized that cancer-type specific aneuploidies, which emerge at early stages of tumor evolution, confer adaptive advantages to the physiological requirements of the tissue of origin. To test this hypothesis, we compared chromosomal aneuploidies reported in the TCGA database to chromosome arm-wide gene expression levels of normal tissues from the GTEx database. We find that cancer-type specific chromosomal aneuploidies mirror differential gene expression levels specific to the respective normal tissues which cannot be explained by copy number alterations of resident cancer driver genes. We propose that cancer-type specific aneuploidies "hard-wire" chromosome arm-wide gene expression levels present in normal tissues, favoring clonal expansion and tumorigenesis. One sentence summaryThe clonal evolution of cancer is initiated by tissue-specific transcriptional requirements

cancer biology↗