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Targeting the fanconi anemia pathway to identify tailored anticancer therapeutics.

Jenkins C, Kan J, Hoatlin ME - Anemia (2012)

Bottom Line: The Fanconi Anemia (FA) pathway consists of proteins involved in repairing DNA damage, including interstrand cross-links (ICLs).The pathway contains an upstream multiprotein core complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and a downstream pathway that converges with a larger network of proteins with roles in homologous recombination and other DNA repair pathways.Inhibiting the FA pathway in ATM deficient cells can be achieved with small molecule inhibitors, suggesting that new cancer therapeutics could be developed by identifying FA pathway inhibitors to treat cancers that contain defects that are synthetic lethal with FA.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Oregon Health and Science University, 3181 SW Sam Jackson Parkway, Portland, OR 97239, USA.

ABSTRACT
The Fanconi Anemia (FA) pathway consists of proteins involved in repairing DNA damage, including interstrand cross-links (ICLs). The pathway contains an upstream multiprotein core complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and a downstream pathway that converges with a larger network of proteins with roles in homologous recombination and other DNA repair pathways. Selective killing of cancer cells with an intact FA pathway but deficient in certain other DNA repair pathways is an emerging approach to tailored cancer therapy. Inhibiting the FA pathway becomes selectively lethal when certain repair genes are defective, such as the checkpoint kinase ATM. Inhibiting the FA pathway in ATM deficient cells can be achieved with small molecule inhibitors, suggesting that new cancer therapeutics could be developed by identifying FA pathway inhibitors to treat cancers that contain defects that are synthetic lethal with FA.

No MeSH data available.


Related in: MedlinePlus

Inhibition of the FA pathway. Strategy for selectively targeting tumor cells by inhibition of the FA pathway by (a) chemosensitization to cross-linking agents or by (b) exploiting specific synthetic lethal interactions.
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fig1: Inhibition of the FA pathway. Strategy for selectively targeting tumor cells by inhibition of the FA pathway by (a) chemosensitization to cross-linking agents or by (b) exploiting specific synthetic lethal interactions.

Mentions: Although FA is rare, understanding the functional role of the FA proteins in context with other DNA damage response pathways will provide broader opportunities for new cancer therapeutics. Two general strategies could accomplish this, as illustrated in Figure 1: inhibiting the FA pathway in tumor cells to sensitize them to cross-linking agents, or by exploiting synthetic lethal relationships. The latter approach depends on inhibiting the FA pathway in tumor cells that are defective for a secondary pathway required for survival in the absence of the FA pathway.


Targeting the fanconi anemia pathway to identify tailored anticancer therapeutics.

Jenkins C, Kan J, Hoatlin ME - Anemia (2012)

Inhibition of the FA pathway. Strategy for selectively targeting tumor cells by inhibition of the FA pathway by (a) chemosensitization to cross-linking agents or by (b) exploiting specific synthetic lethal interactions.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368156&req=5

fig1: Inhibition of the FA pathway. Strategy for selectively targeting tumor cells by inhibition of the FA pathway by (a) chemosensitization to cross-linking agents or by (b) exploiting specific synthetic lethal interactions.
Mentions: Although FA is rare, understanding the functional role of the FA proteins in context with other DNA damage response pathways will provide broader opportunities for new cancer therapeutics. Two general strategies could accomplish this, as illustrated in Figure 1: inhibiting the FA pathway in tumor cells to sensitize them to cross-linking agents, or by exploiting synthetic lethal relationships. The latter approach depends on inhibiting the FA pathway in tumor cells that are defective for a secondary pathway required for survival in the absence of the FA pathway.

Bottom Line: The Fanconi Anemia (FA) pathway consists of proteins involved in repairing DNA damage, including interstrand cross-links (ICLs).The pathway contains an upstream multiprotein core complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and a downstream pathway that converges with a larger network of proteins with roles in homologous recombination and other DNA repair pathways.Inhibiting the FA pathway in ATM deficient cells can be achieved with small molecule inhibitors, suggesting that new cancer therapeutics could be developed by identifying FA pathway inhibitors to treat cancers that contain defects that are synthetic lethal with FA.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Oregon Health and Science University, 3181 SW Sam Jackson Parkway, Portland, OR 97239, USA.

ABSTRACT
The Fanconi Anemia (FA) pathway consists of proteins involved in repairing DNA damage, including interstrand cross-links (ICLs). The pathway contains an upstream multiprotein core complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and a downstream pathway that converges with a larger network of proteins with roles in homologous recombination and other DNA repair pathways. Selective killing of cancer cells with an intact FA pathway but deficient in certain other DNA repair pathways is an emerging approach to tailored cancer therapy. Inhibiting the FA pathway becomes selectively lethal when certain repair genes are defective, such as the checkpoint kinase ATM. Inhibiting the FA pathway in ATM deficient cells can be achieved with small molecule inhibitors, suggesting that new cancer therapeutics could be developed by identifying FA pathway inhibitors to treat cancers that contain defects that are synthetic lethal with FA.

No MeSH data available.


Related in: MedlinePlus