Chromosome Fragile Sites

Abstract

Chromosomal fragile sites are specific loci that preferentially exhibit gaps and breaks on metaphase chromosomes following partial inhibition of DNA synthesis. Their discovery has led to novel findings spanning a number of areas of genetics. Rare fragile sites are seen in a small proportion of individuals and are inherited in a Mendelian manner. Some, such as FRAXA in the FMR1 gene, are associated with human genetic disorders, and their study led to the identification of nucleotide-repeat expansion as a frequent mutational mechanism in humans. In contrast, common fragile sites are present in all individuals and represent the largest class of fragile sites. Long considered an intriguing component of chromosome structure, common fragile sites have taken on novel significance as regions of the genome that are particularly sensitive to replication stress and that are frequently rearranged in tumor cells. In recent years, much progress has been made toward understanding the genomic features of common fragile sites and the cellular processes that monitor and influence their stability. Their study has merged with that of cell cycle checkpoints and DNA repair, and common fragile sites have provided insight into understanding the consequences of replication stress on DNA damage and genome instability in cancer cells.

An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis

“…The identification and functional characterization of FATS suggest the values of dissecting frequent Linkage between p21 and radiation-induced tumorigenesis Z Li et al changes in IR-induced mouse tumors (Mao et al, 2005), which will allow us to uncover new cancer genes involved in early tumorigenesis. We verify that human ortholog of FATS is a CFS gene at FRA10F, one of 76 aphidicolin-induced CFSs that have previously not been cloned and characterized at the molecular level (Durkin and Glover, 2007). CFS stability is regulated by DNA damage checkpoints ATR (Casper et al, 2002), indicating that some level of replication stalling occurs at CFS regions and they could be prone to cause DSBs after radiation treatment in normal cells.…”

“…CFSs are evolutionarily conserved regions that are AT-rich and late replicating (Mangelsdorf et al, 2000;Glover et al, 2005;Schwartz et al, 2006;Zhang and Freudenreich, 2007). In general, CFSs are now being implicated as regions of high genomic instability associated with cancer (Buttel et al, 2004;Durkin and Glover, 2007). However, much less is known about their molecular nature and functional characterization of CFS genes in DNA damage signaling.…”

Common fragile sites in colon cancer cell lines: Role of mismatch repair, RAD51 and poly(ADP-ribose) polymerase-1

“…ondary structures that delay or block the progression of replication forks [3]. CFS contribute to genomic instability because they behave as hotspots for recombination, favouring the evolution of species or tumour formation.…”

“…Under conditions of replication stress, such as that provoked by APC, when the replication fork encounters the fragile site regions, it can stall and slow down the duplicative process or collapse to generate DNA double stand breaks (DSB) [9,10]. The stability of CFS is regulated by many factors, the principal among which is the Ataxia-telangiectasia and Rad3 Related (ATR)-dependent DNA damage checkpoint pathway, because the cells lacking ATR have a dramatic increase in the occurrence of CFS [3,11]. In response to stalled or collapsed replication forks, the ATR kinase acts as DNA damage sensor, which along with downstream effector molecules (e.g.…”

La pauvreté en sites d’initiation de la réplication rend-elle fragile certaines régions du génome ?

“…Ils sont présents chez tous les individus, sont souvent conservés entre les espèces et chevauchent des gènes de grande taille codant pour de petits transcrits. Les SFC sont au nombre d'une centaine dans le génome des lymphocytes humains, mais seul un petit nombre d'entre eux est particulièrement instable et rend compte de plus de 80 % des lésions observées après exposition aux inducteurs [1]. L'intérêt pour les SFC vient de ce qu'ils sont considé-rés comme des sites préférentiels de réarrangements chromosomiques dans différents types de cancers [2,3] et leurs altérations interviendraient à des stades précoces de l'oncogenèse [4].…”