Sunday, June 1, 2025
6/1/2025
Repetitive sequences causing genomic instability and cell dysfunction - PROJECT SUMMARY/ABSTRACT The major goal of our research program is to unravel mechanisms and detect errors during processing of repetitive DNA or RNA sequences that could lead to genomic instability and cell dysfunction. A considerable fraction of the genome in nearly all organisms consists of repetitive DNA sequences. It has been suggested that these repetitive sequences play a role in several cellular processes. However, repetitive DNA sequences can adopt non-conventional DNA and RNA structures, which can be a challenge for the DNA replication, transcription and translation machinery to travel through and process correctly. Prolonged stalling of the replication forks in human cells can have severe consequences, such as genome instability that include chromosome fragility, genomic mutations and expansions of these repeat sequences. Also, repetitive sequences located in the mRNA can interfere with translation and lead to aberrant protein expression. Several neurological and muscular diseases are caused by repeat expansions. To avoid genomic instability at repetitive sequences human cells employ several mechanisms to prevent genomic alterations, cell death and diseases. BRCA1 is one of such proteins, which is involved in several molecular pathways including DNA repair and DNA replication. However, it is not clear how much BRCA1 is needed to fulfill all BRCA1 functions properly, and which back-up mechanisms are activated in cells with 50% of BRCA1 expression. In addition, repetitive sequences in the mRNA can trigger repeat-associated non-UTG (RAN)-initiated translation leading to the generation of abnormal polypeptides that form inclusions in human cells and cause several neurological, ovarian and muscular disorders. However, the mechanisms leading to cell dysfunction, cell death and repeat expansions induced by these abnormal inclusions are not clearly understood. In addition, it is not known which trans factors and mechanisms promote repeat expansion in human cells. Aberrant inclusions could sequester or dysregulate nuclear repair proteins causing DNA damage, cell dysfunction and apoptosis. In this MIRA application we seek to determine these mechanisms and DNA repair pathways leading to genomic instability in proliferating cells and large repeat expansion in non-proliferating human oocytes. The expected outcome of this studies will be new knowledge how repetitive DNA and RNA sequences induce genomic instability and cell dysfunction in so far rare studied human cells.
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