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Transcriptional and Chromatin Disorientation Associated with BRCA2 Inactivation


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Authors

Gupta, Komal 

Abstract

Monoallelic germline mutations in the tumour suppressor gene BRCA2 predispose to breast, ovarian, prostate and pancreatic cancer. Functionally, BRCA2 protein is involved in genome integrity maintenance via homologous recombination repair, DNA replication fork protection, and R-loop resolution. However, the mechanism by which BRCA2 inactivation causes cancer remains unclear. In this study, using RNA-seq and ATAC-seq I investigated whether BRCA2 acts as a tumour suppressor via regulating the transcriptional and chromatin organization. Using RNA seq datasets from BRCA2 mutant MCF10A cell lines and TCGA breast cancers, I report that BRCA2 inactivation leads to dysregulation of genes involved in the cell cycle, DNA repair, and replication. Strikingly, oncogene MYC targets are upregulated upon biallelic, but not monoallelic BRCA2 loss, provoking the hypothesis that MYC signalling activation is accompanied by the loss of the second BRCA2 allele. Interestingly, ATAC seq in BRCA2 WT and mutant cells to explore the effect on chromatin organization revealed that BRCA2 inactivation leads to increased heterochromatin accessibility. Further, investigating the underlying epigenetic alterations showed that BRCA2 deficient cells had a loss of repressive H3K9me3 mark which was associated with chromatin accessibility. Importantly, this chromatin de-repression was accompanied by increased expression of repetitive RNAs, which have been implicated in inducing DNA damage, genomic instability, and chromosomal segregation defects. However, the causality between chromatin changes and de-repression of repetitive RNA is not clear yet. Lastly, I explored ways to exploit the above findings to detect BRCA2 loss of heterozygosity among patients using cell-free DNA. Overall, these findings provide new insights into the tumour suppressive role of BRCA2 in maintaining global heterochromatin integrity and repetitive DNA repression which engenders novel oncogenic driver mechanisms in BRCA2 loss-associated cancers.

Description

Date

2023-06-01

Advisors

Venkitaraman, Ashok

Keywords

BRCA2, Cancer, Chromatin organization, Transcriptomics

Qualification

Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge
Sponsorship
Cambridge Trust Commonwealth Scholarship