Molecular mechanisms protecting centromeres from self-sabotage and implications for cancer therapy

Abstract

Centromeres play a crucial role in DNA segregation by mediating the cohesion and separation of sister chromatids during cell division. Centromere dysfunction, breakage or compromised centromeric integrity can generate aneuploidies and chromosomal instability, which are cellular features associated with cancer initiation and progression. Maintaining centromere integrity is thus essential for genome stability. However, the centromere itself is prone to DNA breaks, likely due to its intrinsically fragile nature. Centromeres are complex genomic loci that are composed of highly repetitive DNA sequences and secondary structures and require the recruitment and homeostasis of a centromere-associated protein network. The molecular mechanisms engaged to preserve centromere inherent structure and respond to centromeric damage are not fully understood and remain a subject of ongoing research. In this article, we provide a review of the currently known factors that contribute to centromeric dysfunction and the molecular mechanisms that mitigate the impact of centromere damage on genome stability. Finally, we discuss the potential therapeutic strategies that could arise from a deeper understanding of the mechanisms preserving centromere integrity.

Use of Enzymatically Converted Cell-Free DNA (cfDNA) Data for Copy Number Variation-Linked Fragmentation Analysis Allows for Early Colorectal Cancer Detection

“…Interestingly, the chromosome 18 features found by our study were not located around previously indicated genes along the long arm of chromosome 18 but rather located around centromeres. Centromere dysfunction, breakage, or compromised centromeric integrity has been reported to be linked to cancer initiation and progression as it leads to chromosomal instability and aneuploidies [ 45 ].…”

WEE1 kinase inhibition triggers severe chromosome pulverization in aneuploid cells

“…In situations where cells undergo premature entry into mitosis while having damaged and under-replicated genomes, one would expect late-replicating regions such as centromeric DNA to remain incompletely replicated despite cell cycle progression. Notably, proteins implicated in DNA repair and replication stress pathways may become enriched during centromeric replication 41 , as these genomic loci are fragile and challenging to replicate. The DNA2 helicase/nuclease, a putative substrate of CDK1 42 , has high affinity for centromeric DNA 43 .…”

Editorial: DNA repair and nucleic acid therapeutics in cancer

“…Nassar et al. bring insight into the protection mechanisms essential to maintain centromeres and how these mechanisms may be exploited for cancer selective treatment options ( 50 ). Telomeres are a unique genomic structure that depends on telomerase, a specialized reverse transcriptase required for telomere maintenance.…”