Telomere Fragility and MiDAS: Managing the Gaps at the End of the Road

Abstract

Telomeres present inherent difficulties to the DNA replication machinery due to their repetitive sequence content, formation of non-B DNA secondary structures, and the presence of the nucleo-protein t-loop. Especially in cancer cells, telomeres are hot spots for replication stress, which can result in a visible phenotype in metaphase cells termed “telomere fragility”. A mechanism cells employ to mitigate replication stress, including at telomeres, is DNA synthesis in mitosis (MiDAS). While these phenomena are both observed in mitotic cells, the relationship between them is poorly understood; however, a common link is DNA replication stress. In this review, we will summarize what is known to regulate telomere fragility and telomere MiDAS, paying special attention to the proteins which play a role in these telomere phenotypes.

Natural genomic variation in rice blast genomes is associated with specific heterochromatin modifications

“…Therefore, a potential mechanisms for the observed differences between the associations of SNPs and INDELs with histone marks could be that the different chromatin states influence DNA repair pathway choice in a given region, and thus alter the frequency and type of mutations (108). However, these associations are confounded by the tendency for TEs and effectors to be in subtelomeric regions of chromosomes, which are documented to be fragile due to highly repetitive sequences (109). Further studies to isolate and test specific factors controlling the frequency and spectrum of mutations are needed to understand cause and effect (7).…”

Telomere-related DNA damage response pathways in cancer therapy: prospective targets

“…The shelterin complex at the telomere ends forms a protective T-loop, which alters the end of the chromosome similar to that of the recombinant D-loop, thus concealing the 3′one-stranded DNA overhanging ends and preventing the false activation of DDR. Most somatic cells have progressively shorter telomeres, but carcinomas can sustain telomere length by upregulating telomerase activity or using the ALT mechanism ( Barnes et al, 2023 ). How does DDR at telomere ends in tumors protect cells from overproliferation and promote tumorigenesis?…”

PARP2 promotes Break Induced Replication-mediated telomere fragility in response to replication stress

“…Telomeres protect linear chromosomes by forming a t-loop with the assistance of a specific protein complex named shelterin. Due to their G-rich repetitive sequences, telomeres are inherently vulnerable to replication stress, as they can form stable G-quadruplex structures (G4s) that hinder replication fork progression 34 , 35 . Telomeric TTAGGG repeats are also highly sensitive to oxidative stress.…”