DNA Packaging Defects in Breast Cancer
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Recently the human genome was reported to be approximately 3.15 billion pairs of DNA. The amount and length of this DNA is staggering, especially considering the incredibly tiny size of the cell's nucleus. Apparently, there are highly regulated ways that the DNA in the 23 pairs of chromosomes is packaged. One aspect of this packaging is already well known. It involves the histone proteins, and they combine with DNA to form a microscopic structure that looks likes "beads- on-a-string" (nucelosomes)- each nucleosome contains 146 base pairs of DNA, and it is repeated every 200 base pairs on average. Our laboratory studies a higher level of DNA organization that involves the attachment of specific stretches of DNA (called matrix attachment region or MARs) to a skeletal framework made of proteins and RNA molecules inside the nucleus. This attachment of DNA, which results in separating DNA into a series of loop domains, is mediated by a specific group of proteins in the nucleus. This loop organization is thought to be important not only for DNA compaction; it may also allow specific sequences to be "read" by enzymes in a timely manner when making proteins or replicating the DNA. In other words, this "packaging" may facilitate bookkeeping of the DNA's information.
 
 
 
 
 
 
 
 Using previous support from the BCRP we have found a protein that binds to MARs is greatly increased in breast cancer cells. This protein was identified as poly (ADP-ribose) polymerse (PARP), which is known to play a role in DNA damage repair. Our new results strongly suggest that PARP also plays a key role in the DNA packaging of breast cancer cells through binding to MARs. Our hypotheses are that (i) PARP plays an essential role in the genome organization in breast cancer, and (ii) PARP is involved in the activation of genes related to growth and metastasis characteristic of breast cancer. Using the present BCRP support we will test these ideas by deleting PARP from aggressive breast cancer cells and determining the effect on both cell invasion properties and cancer-specific gene expression. In addition, we will use the newly developed techniques in gene microarrays to compare breast cancer cells having PARP present or those having PARP deleted. This will give us an initial read-out of the global effects of PARP in breast cancer. Our idea is that cancer cells may express these proteins that bind to MARs at different levels compared to normal cells, to organize their DNA to maintain their growth rate and invasive characteristics. Finally, we will use a mouse model system for human breast cancer. These mice are engineered to overproduce an oncogene (a gene that turns normal cells cancerous) so as to spontaneously form breast cancer and metastasizing to the lung. We will further engineer these mice to not produce PARP. We will then ask whether breast cancer can still develop and/or metastasize under these conditions.
 
 
 
 
 
 
 
 These studies will provide important information as to how invasive breast cancer cells manage to maintain their aggressive phenotype. This information will also be useful for developing breast cancer therapies in the future.