Limits...
Are common fragile sites merely structural domains or highly organized "functional" units susceptible to oncogenic stress?

Georgakilas AG, Tsantoulis P, Kotsinas A, Michalopoulos I, Townsend P, Gorgoulis VG - Cell. Mol. Life Sci. (2014)

Bottom Line: Given that a number of oncogenes and tumor suppressors are located within CFSs, a question that emerges is whether fragility in these regions is only a structural "passive" incident or an event with a profound biological effect.By analyzing data from various libraries, like miRbase and ENCODE, we show a prevalence of various cancer-related genes, miRNAs, and regulatory binding sites, such as CTCF within CFSs.We propose that CFSs are not only susceptible structural domains, but highly organized "functional" entities that when targeted, severe repercussion for cell homeostasis occurs.

View Article: PubMed Central - PubMed

Affiliation: Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens (NTUA), Zografou, 15780, Athens, Greece.

ABSTRACT
Common fragile sites (CFSs) are regions of the genome with a predisposition to DNA double-strand breaks in response to intrinsic (oncogenic) or extrinsic replication stress. CFS breakage is a common feature in carcinogenesis from its earliest stages. Given that a number of oncogenes and tumor suppressors are located within CFSs, a question that emerges is whether fragility in these regions is only a structural "passive" incident or an event with a profound biological effect. Furthermore, there is sparse evidence that other elements, like non-coding RNAs, are positioned with them. By analyzing data from various libraries, like miRbase and ENCODE, we show a prevalence of various cancer-related genes, miRNAs, and regulatory binding sites, such as CTCF within CFSs. We propose that CFSs are not only susceptible structural domains, but highly organized "functional" entities that when targeted, severe repercussion for cell homeostasis occurs.

Show MeSH

Related in: MedlinePlus

Model proposing that CFS apart from contributing to GI exert wider biological effects during cancer development. CFSs are preferentially affected from the earliest precancerous lesions, in response to OIRS, conferring to GI. A wide spectrum of coding and non-coding elements are present within CFSs. Cancer-related genes and miRs may be affected from such early precancerous stages, therefore possibly exerting a strong pressure for malignant progression. This pressure is also reinforced by alterations and imbalances in the binding elements and histone patterns, respectively, in the CFSs. Furthermore, collectively, all of these alterations may further affect in an “avalanche” mode not only the stability of the CFSs, but overall of the genome. As the anti-tumor barriers are gradually overwhelmed, this avalanche effect may function in a positive feedback mode to promote cancer
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4232749&req=5

Fig3: Model proposing that CFS apart from contributing to GI exert wider biological effects during cancer development. CFSs are preferentially affected from the earliest precancerous lesions, in response to OIRS, conferring to GI. A wide spectrum of coding and non-coding elements are present within CFSs. Cancer-related genes and miRs may be affected from such early precancerous stages, therefore possibly exerting a strong pressure for malignant progression. This pressure is also reinforced by alterations and imbalances in the binding elements and histone patterns, respectively, in the CFSs. Furthermore, collectively, all of these alterations may further affect in an “avalanche” mode not only the stability of the CFSs, but overall of the genome. As the anti-tumor barriers are gradually overwhelmed, this avalanche effect may function in a positive feedback mode to promote cancer

Mentions: Common fragile sites have long been considered vulnerable breakage sites in the genome in response to RS from extrinsic factors. Their fragility has also been associated with GI in cancer development. As we have previously shown, CFSs are preferentially affected from the earliest precancerous lesions, in response to OIRS [2, 4]. In the current work, we first performed a review on the heterogeneity and fragility mechanisms affecting these sites. Next, by applying bioinformatic tools and exploiting available information in various databases, like the KEGG, miRbase, and ENCODE, we show a prevalence of various cancer-related genes, miRs, binding elements, and histone modifications in CFSs (Figs. 1, 3). The presence of such a wide spectrum of coding and non-coding elements changes the view on CFSs content and their nature itself. Given that CFSs are altered from the earliest stages in cancer, their impact on cancer development may be more profound than simply participating in the emergence of GI. On one hand, cancer-related genes and miRs may be affected from such early precancerous stages, therefore possibly exerting a strong pressure for malignant progression (Fig. 3). On the other hand, this pressure is also reinforced by alterations and imbalances in the binding elements and histone patterns, respectively, in the CFSs. Furthermore, collectively, all these alterations may further affect in an “avalanche” mode not only the stability of the CFSs, but overall of the genome (Figs. 1, 3). Therefore, as the anti-tumor barriers are gradually overwhelmed, this avalanche effect may function in a positive feedback mode to promote cancer. An important question that emerges is why CFSs are not selected for elimination from the genome, but are rather conserved features in mammals? A tempting but speculative answer is that by locating a set of important coding and non-coding elements in regions that replicate late and/or with delay and thus are prone to instability, they may function as alarm sensors scattered throughout the genome in various chromosomes, to signify detrimental effects from the RS on the cell. As long as the mammalian checkpoints and repair mechanisms are not compromised, cells can monitor and protect their genome and functional integrity through such a dynamic interaction. Nevertheless, this imposes the risk that if the checkpoints and the anti-tumor barriers gradually fail, tumor promotion ensues (Fig. 3). As we were able to examine only a small subset of binding elements and histone modifications from the ENCODE and the miRbase is constantly expanding, in the future more in-depth studies are required to obtain a comprehensive picture of CFSs and on their role in cancer. Overall, CFSs may not be merely structural domains vulnerable only to breakage but highly organized “functional” units that may have deeper biological consequences for the cell when affected.Fig. 3


Are common fragile sites merely structural domains or highly organized "functional" units susceptible to oncogenic stress?

Georgakilas AG, Tsantoulis P, Kotsinas A, Michalopoulos I, Townsend P, Gorgoulis VG - Cell. Mol. Life Sci. (2014)

Model proposing that CFS apart from contributing to GI exert wider biological effects during cancer development. CFSs are preferentially affected from the earliest precancerous lesions, in response to OIRS, conferring to GI. A wide spectrum of coding and non-coding elements are present within CFSs. Cancer-related genes and miRs may be affected from such early precancerous stages, therefore possibly exerting a strong pressure for malignant progression. This pressure is also reinforced by alterations and imbalances in the binding elements and histone patterns, respectively, in the CFSs. Furthermore, collectively, all of these alterations may further affect in an “avalanche” mode not only the stability of the CFSs, but overall of the genome. As the anti-tumor barriers are gradually overwhelmed, this avalanche effect may function in a positive feedback mode to promote cancer
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4232749&req=5

Fig3: Model proposing that CFS apart from contributing to GI exert wider biological effects during cancer development. CFSs are preferentially affected from the earliest precancerous lesions, in response to OIRS, conferring to GI. A wide spectrum of coding and non-coding elements are present within CFSs. Cancer-related genes and miRs may be affected from such early precancerous stages, therefore possibly exerting a strong pressure for malignant progression. This pressure is also reinforced by alterations and imbalances in the binding elements and histone patterns, respectively, in the CFSs. Furthermore, collectively, all of these alterations may further affect in an “avalanche” mode not only the stability of the CFSs, but overall of the genome. As the anti-tumor barriers are gradually overwhelmed, this avalanche effect may function in a positive feedback mode to promote cancer
Mentions: Common fragile sites have long been considered vulnerable breakage sites in the genome in response to RS from extrinsic factors. Their fragility has also been associated with GI in cancer development. As we have previously shown, CFSs are preferentially affected from the earliest precancerous lesions, in response to OIRS [2, 4]. In the current work, we first performed a review on the heterogeneity and fragility mechanisms affecting these sites. Next, by applying bioinformatic tools and exploiting available information in various databases, like the KEGG, miRbase, and ENCODE, we show a prevalence of various cancer-related genes, miRs, binding elements, and histone modifications in CFSs (Figs. 1, 3). The presence of such a wide spectrum of coding and non-coding elements changes the view on CFSs content and their nature itself. Given that CFSs are altered from the earliest stages in cancer, their impact on cancer development may be more profound than simply participating in the emergence of GI. On one hand, cancer-related genes and miRs may be affected from such early precancerous stages, therefore possibly exerting a strong pressure for malignant progression (Fig. 3). On the other hand, this pressure is also reinforced by alterations and imbalances in the binding elements and histone patterns, respectively, in the CFSs. Furthermore, collectively, all these alterations may further affect in an “avalanche” mode not only the stability of the CFSs, but overall of the genome (Figs. 1, 3). Therefore, as the anti-tumor barriers are gradually overwhelmed, this avalanche effect may function in a positive feedback mode to promote cancer. An important question that emerges is why CFSs are not selected for elimination from the genome, but are rather conserved features in mammals? A tempting but speculative answer is that by locating a set of important coding and non-coding elements in regions that replicate late and/or with delay and thus are prone to instability, they may function as alarm sensors scattered throughout the genome in various chromosomes, to signify detrimental effects from the RS on the cell. As long as the mammalian checkpoints and repair mechanisms are not compromised, cells can monitor and protect their genome and functional integrity through such a dynamic interaction. Nevertheless, this imposes the risk that if the checkpoints and the anti-tumor barriers gradually fail, tumor promotion ensues (Fig. 3). As we were able to examine only a small subset of binding elements and histone modifications from the ENCODE and the miRbase is constantly expanding, in the future more in-depth studies are required to obtain a comprehensive picture of CFSs and on their role in cancer. Overall, CFSs may not be merely structural domains vulnerable only to breakage but highly organized “functional” units that may have deeper biological consequences for the cell when affected.Fig. 3

Bottom Line: Given that a number of oncogenes and tumor suppressors are located within CFSs, a question that emerges is whether fragility in these regions is only a structural "passive" incident or an event with a profound biological effect.By analyzing data from various libraries, like miRbase and ENCODE, we show a prevalence of various cancer-related genes, miRNAs, and regulatory binding sites, such as CTCF within CFSs.We propose that CFSs are not only susceptible structural domains, but highly organized "functional" entities that when targeted, severe repercussion for cell homeostasis occurs.

View Article: PubMed Central - PubMed

Affiliation: Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens (NTUA), Zografou, 15780, Athens, Greece.

ABSTRACT
Common fragile sites (CFSs) are regions of the genome with a predisposition to DNA double-strand breaks in response to intrinsic (oncogenic) or extrinsic replication stress. CFS breakage is a common feature in carcinogenesis from its earliest stages. Given that a number of oncogenes and tumor suppressors are located within CFSs, a question that emerges is whether fragility in these regions is only a structural "passive" incident or an event with a profound biological effect. Furthermore, there is sparse evidence that other elements, like non-coding RNAs, are positioned with them. By analyzing data from various libraries, like miRbase and ENCODE, we show a prevalence of various cancer-related genes, miRNAs, and regulatory binding sites, such as CTCF within CFSs. We propose that CFSs are not only susceptible structural domains, but highly organized "functional" entities that when targeted, severe repercussion for cell homeostasis occurs.

Show MeSH
Related in: MedlinePlus