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Mass General Hospital Cancer Center treats patients with many cancer types. To learn more about the different cancer types that can be treated at the Cancer Center, please visit the Cancer Center website at the following page: http://www.massgeneral.org/cancer/services/
Expand Collapse DNA-PKcs  - General Description The maintenance of intact, correctly sequenced DNA is vital to the life of a cell. If there are mistakes made in replicating DNA before cell division, subsequent daughter cells will have inaccurate DNA, and may either die or carry mutations that can contribute to the development of cancer. For this reason, cells have evolved multiple pathways to repair mistakes in-or damage to- DNA. The specific repair pathway used by the cell depends on the type of DNA damage that has occurred. The types of DNA repair that we are focusing on relate directly to cancer. These involve a break in BOTH strands of DNA, which can be the result of ionizing radiation or other DNA damaging agents. This type of DNA damage is called Double Strand Breaks (DSB’s). There are two main pathways used by cells to repair DSB’s in their DNA. One is Homologous Recombination (HR), which is explained in detail if you select either the “ATM” or “ATR” gene from the initial list of genes on this web page. A second type of DSB DNA repair is called Non-Homologous End Joining (NHEJ). It is this second type of DSB repair that this section of the web site focuses on. Many proteins are involved in the complex NHEJ pathway to repair DSB’s in DNA. The graphic above depicts a simplified scheme outlining NHEJ. (If you click on the graphic, it enlarges, making it easier to follow). While NHEJ is complicated, the DSB depicted at the top right corner of the graphic is acted upon by a series of proteins in the circle of steps shown that ultimately lead to the complete repair of the DSB in the DNA. When a DSB arises, Ku70 and Ku80 sense the broken ends of the DSB, and together bind both sides of the broken ends. The Ku proteins bound to DNA form a complex that recruits the other proteins that are involved in the NHEJ repair process. The Ku:DNA complex recruits DNA-PKcs, (DNA-dependent Protein Kinase catalytic subunit) onto the break points. When DNA-PKcs binds to the DNA on the Ku:DNA complex, the DNA-PKcs changes its shape, and this conformational change activates the protein to perform its enzyme function as a kinase. A protein called Artemis then joins the complex, and processes the broken DNA ends to get them ready for being rejoined in a process called ligation. The ligation or re-joining of the ends is accomplished by a group of proteins acting together, XRCC4, XLF, and Lig4. Ligation of the ends results in the previously broken ends being rejoined, repairing the DSB and restoring the integrity of the DNA. Mutations in some of the proteins involved in this DSB repair process results in an inability of the cell to repair damaged or broken DNA. The accumulation of unrepaired DNA damage can result in the development of cancer. Specific mutations in some tumors have been found in the DNA-PKcs protein. Defects in the genes encoding other proteins in the NHEJ pathway have also been found to be mutated in some cancers. Testing for mutations in the many genes involved in NHEJ is available through the MGH genetics lab. Treatment as well as clinical trials studying new drugs that target defects in the DNA repair proteins or that take advantage of the loss of the NHEJ repair pathway due to mutations in these genes are available at the MGH Cancer Center. The maintenance of intact, correctly sequenced DNA is vital to the life of a cell. If there are mistakes made in replicating DNA before cell division, subsequent daughter cells will have inaccurate DNA, and may either die or carry mutations that can contribute to the development of cancer. For this reason, cells have evolved multiple pathways to repair mistakes in-or damage to- DNA. The specific repair pathway used by the cell depends on the type of DNA damage that has occurred. The types of DNA repair that we are focusing on relate directly to cancer. These involve a break in BOTH strands of DNA, which can be the result of ionizing radiation or other DNA damaging agents. This type of DNA damage is called Double Strand Breaks (DSB’s). There are two main pathways used by cells to repair DSB’s in their DNA. One is Homologous Recombination (HR), which is explained in detail if you select either the “ATM” or “ATR” gene from the initial list of genes on this web page. A second type of DSB DNA repair is called Non-Homologous End Joining (NHEJ). It is this second type of DSB repair that this section of the web site focuses on. Many proteins are involved in the complex NHEJ pathway to repair DSB’s in DNA. The graphic above depicts a simplified scheme outlining NHEJ. (If you click on the graphic, it enlarges, making it easier to follow). While NHEJ is complicated, the DSB depicted at the top right corner of the graphic is acted upon by a series of proteins in the circle of steps shown that ultimately lead to the complete repair of the DSB in the DNA. When a DSB arises, Ku70 and Ku80 sense the broken ends of the DSB, and together bind both sides of the broken ends. The Ku proteins bound to DNA form a complex that recruits the other proteins that are involved in the NHEJ repair process. The Ku:DNA complex recruits DNA-PKcs, (DNA-dependent Protein Kinase catalytic subunit) onto the break points. When DNA-PKcs binds to the DNA on the Ku:DNA complex, the DNA-PKcs changes its shape, and this conformational change activates the protein to perform its enzyme function as a kinase. A protein called Artemis then joins the complex, and processes the broken DNA ends to get them ready for being rejoined in a process called ligation. The ligation or re-joining of the ends is accomplished by a group of proteins acting together, XRCC4, XLF, and Lig4. Ligation of the ends results in the previously broken ends being rejoined, repairing the DSB and restoring the integrity of the DNA. Mutations in some of the proteins involved in this DSB repair process results in an inability of the cell to repair damaged or broken DNA. The accumulation of unrepaired DNA damage can result in the development of cancer. Specific mutations in some tumors have been found in the DNA-PKcs protein. Defects in the genes encoding other proteins in the NHEJ pathway have also been found to be mutated in some cancers. Testing for mutations in the many genes involved in NHEJ is available through the MGH genetics lab. Treatment as well as clinical trials studying new drugs that target defects in the DNA repair proteins or that take advantage of the loss of the NHEJ repair pathway due to mutations in these genes are available at the MGH Cancer Center.
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The maintenance of intact, correctly sequenced DNA is vital to the life of a cell. If there are mistakes made in replicating DNA before cell division, subsequent daughter cells will have inaccurate DNA, and may either die or carry mutations that can contribute to the development of cancer. For this reason, cells have evolved multiple pathways to repair mistakes in-or damage to- DNA. The specific repair pathway used by the cell depends on the type of DNA damage that has occurred. The types of DNA repair that we are focusing on relate directly to cancer. These involve a break in BOTH strands of DNA, which can be the result of ionizing radiation or other DNA damaging agents. This type of DNA damage is called Double Strand Breaks (DSB’s). There are two main pathways used by cells to repair DSB’s in their DNA. One is Homologous Recombination (HR), which is explained in detail if you select either the “ATM” or “ATR” gene from the initial list of genes on this web page. A second type of DSB DNA repair is called Non-Homologous End Joining (NHEJ). It is this second type of DSB repair that this section of the web site focuses on.

Many proteins are involved in the complex NHEJ pathway to repair DSB’s in DNA. The graphic above depicts a simplified scheme outlining NHEJ. (If you click on the graphic, it enlarges, making it easier to follow). While NHEJ is complicated, the DSB depicted at the top right corner of the graphic is acted upon by a series of proteins in the circle of steps shown that ultimately lead to the complete repair of the DSB in the DNA.

When a DSB arises, Ku70 and Ku80 sense the broken ends of the DSB, and together bind both sides of the broken ends. The Ku proteins bound to DNA form a complex that recruits the other proteins that are involved in the NHEJ repair process. The Ku:DNA complex recruits DNA-PKcs, (DNA-dependent Protein Kinase catalytic subunit) onto the break points. When DNA-PKcs binds to the DNA on the Ku:DNA complex, the DNA-PKcs changes its shape, and this conformational change activates the protein to perform its enzyme function as a kinase. A protein called Artemis then joins the complex, and processes the broken DNA ends to get them ready for being rejoined in a process called ligation. The ligation or re-joining of the ends is accomplished by a group of proteins acting together, XRCC4, XLF, and Lig4. Ligation of the ends results in the previously broken ends being rejoined, repairing the DSB and restoring the integrity of the DNA.

Mutations in some of the proteins involved in this DSB repair process results in an inability of the cell to repair damaged or broken DNA. The accumulation of unrepaired DNA damage can result in the development of cancer. Specific mutations in some tumors have been found in the DNA-PKcs protein. Defects in the genes encoding other proteins in the NHEJ pathway have also been found to be mutated in some cancers.

Testing for mutations in the many genes involved in NHEJ is available through the MGH genetics lab. Treatment as well as clinical trials studying new drugs that target defects in the DNA repair proteins or that take advantage of the loss of the NHEJ repair pathway due to mutations in these genes are available at the MGH Cancer Center.
The maintenance of intact, correctly sequenced DNA is vital to the life of a cell. If there are mistakes made in replicating DNA before cell division, subsequent daughter cells will have inaccurate DNA, and may either die or carry mutations that can contribute to the development of cancer. For this reason, cells have evolved multiple pathways to repair mistakes in-or damage to- DNA. The specific repair pathway used by the cell depends on the type of DNA damage that has occurred. The types of DNA repair that we are focusing on relate directly to cancer. These involve a break in BOTH strands of DNA, which can be the result of ionizing radiation or other DNA damaging agents. This type of DNA damage is called Double Strand Breaks (DSB’s). There are two main pathways used by cells to repair DSB’s in their DNA. One is Homologous Recombination (HR), which is explained in detail if you select either the “ATM” or “ATR” gene from the initial list of genes on this web page. A second type of DSB DNA repair is called Non-Homologous End Joining (NHEJ). It is this second type of DSB repair that this section of the web site focuses on.

Many proteins are involved in the complex NHEJ pathway to repair DSB’s in DNA. The graphic above depicts a simplified scheme outlining NHEJ. (If you click on the graphic, it enlarges, making it easier to follow). While NHEJ is complicated, the DSB depicted at the top right corner of the graphic is acted upon by a series of proteins in the circle of steps shown that ultimately lead to the complete repair of the DSB in the DNA.

When a DSB arises, Ku70 and Ku80 sense the broken ends of the DSB, and together bind both sides of the broken ends. The Ku proteins bound to DNA form a complex that recruits the other proteins that are involved in the NHEJ repair process. The Ku:DNA complex recruits DNA-PKcs, (DNA-dependent Protein Kinase catalytic subunit) onto the break points. When DNA-PKcs binds to the DNA on the Ku:DNA complex, the DNA-PKcs changes its shape, and this conformational change activates the protein to perform its enzyme function as a kinase. A protein called Artemis then joins the complex, and processes the broken DNA ends to get them ready for being rejoined in a process called ligation. The ligation or re-joining of the ends is accomplished by a group of proteins acting together, XRCC4, XLF, and Lig4. Ligation of the ends results in the previously broken ends being rejoined, repairing the DSB and restoring the integrity of the DNA.

Mutations in some of the proteins involved in this DSB repair process results in an inability of the cell to repair damaged or broken DNA. The accumulation of unrepaired DNA damage can result in the development of cancer. Specific mutations in some tumors have been found in the DNA-PKcs protein. Defects in the genes encoding other proteins in the NHEJ pathway have also been found to be mutated in some cancers.

Testing for mutations in the many genes involved in NHEJ is available through the MGH genetics lab. Treatment as well as clinical trials studying new drugs that target defects in the DNA repair proteins or that take advantage of the loss of the NHEJ repair pathway due to mutations in these genes are available at the MGH Cancer Center.
PubMed ID's
PMC4184981
Expand Collapse All Mutations  in DNA-PKcs

Genetic alterations in the gene PRKDC, which encodes DNA-Protein Kinase catalytic subunit (DNA-PKcs) are most often point mutations. These mutations in the DNA result in changes in the normal amino acid sequence of the protein. Amino acid sequence changes in the DNA-PKcs protein can cause either a truncation or shortened version of the protein, or, in the case of an incorrect amino acid sequence can cause the protein to fold into its 3 dimensional structure incorrectly. Incorrectly folded or truncated versions of DNA-PKcs cannot perform their normal function in NHEJ DNA repair when DSBs occur. Less frequently, the copy number of the PRKDC gene has been found to be increased in some tumors. Any of these genetic alterations causes an abnormal accumulation of DSBs or other DNA damage in the cell, and leads to the development of cancer.
Genetic alterations in the gene PRKDC, which encodes DNA-Protein Kinase catalytic subunit (DNA-PKcs) are most often point mutations. These mutations in the DNA result in changes in the normal amino acid sequence of the protein. Amino acid sequence changes in the DNA-PKcs protein can cause either a truncation or shortened version of the protein, or, in the case of an incorrect amino acid sequence can cause the protein to fold into its 3 dimensional structure incorrectly. Incorrectly folded or truncated versions of DNA-PKcs cannot perform their normal function in NHEJ DNA repair when DSBs occur. Less frequently, the copy number of the PRKDC gene has been found to be increased in some tumors. Any of these genetic alterations causes an abnormal accumulation of DSBs or other DNA damage in the cell, and leads to the development of cancer.

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Your Matched Clinical Trials

Trial Matches: (G) - Gene, (M) - Mutation
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MGH has many open clinical trials for other cancers not shown on the Targeted Cancer Care website. They can be found on the MassGeneral.org clinical trials search page.

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