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Autophagy works in the cell nucleus to guard against the start of cancer, according to research published in Nature.
The study showed, for the first time, that autophagy is used to digest nuclear material in mammalian cells.
“We found that the molecular machinery of autophagy guides the degradation of components of the nuclear lamina in mammals,” said study author Shelley Berger, PhD, of the University of Pennsylvania in Philadelphia.
The nuclear lamina is a network of protein filaments lining the inside of the membrane of the nucleus. It provides mechanical support to the nucleus and regulates gene expression by making some areas of the genome less or more available to be transcribed into messenger RNA.
Previous studies showed that the autophagy protein LC3 can be found in the nucleus, but it was not clear why, as the protein was thought to be functional in the cytoplasm. Study author Zhixun Dou, PhD, came to the Berger lab with this in mind.
At the same time, Peter Adams, PhD, from the University of Glasgow in Scotland, published a study on the breakdown of the nuclear lamina in which he observed a peculiar protrusion, or blebbing, of the nuclear envelope into the cytoplasm. These blebs contained DNA, nuclear lamina proteins, and chromatin.
This evidence led the Berger and Adams labs to work together to find out what was going on.
Using biochemical and sequencing methods, Dr Dou found that laminB1, a key component of the nuclear lamina, and LC3 were contacting each other in the same places on chromatin.
In fact, LC3 and laminB1 are physically bound to each other. LC3 directly interacts with lamin B1 and binds to lamin-associated domains on chromatin.
Autophagy in cancer and aging
The investigators found that, in response to cellular stress that can cause cancer, LC3, chromatin, and laminB1 migrate from the nucleus—via the nuclear blebs—into the cytoplasm and are eventually targeted for disposal.
This breakdown of laminB1 and other nuclear material leads to senescence. The Berger and Adams labs have been studying senescence in conjunction with cancer for quite some time. One way human cells protect themselves from becoming cancerous is to accelerate aging via senescence so the cells can no longer replicate.
The team showed that when a cell’s DNA is damaged or an oncogene is activated (both of which can cause cancer), a normal cell triggers the digestion of nuclear lamina by autophagy, which promotes senescence. Inhibiting this digestion of nuclear material weakens the senescence program and leads to cancerous growth of cells.
“The nucleus is the headquarters of a cell,” Dr Dou said. “When a cell receives a danger alarm, amazingly, it deliberately messes up its headquarters, with the consequence that many functions are completely stopped for the cell. Our study suggests this new function of autophagy is a guarding mechanism that protects cells from becoming cancerous.”
The investigators noted that senescence is associated with normal aging, and senescent cells accumulate in aged tissues, which impair the normal functions of the tissue and contribute to age-related diseases. While autophagy in the nucleus is able to restrain cancer, this machinery is improperly turned on during normal aging.
“There is a short-term ‘tactical’ advantage, but a long-term ‘strategic’ defeat,” Dr Berger explained. “This mechanism makes a normal cell, even without cancer stress, get old much faster, and in a detrimental way.”
In support of this notion, the investigators found that, in late-middle-aged normal cells, blocking the autophagy-driven breakdown of the nuclear lamina can make cells live 60% longer. In fact, the team said the age extension is equivalent to a 70-year-old person living to over 110 years old.
Looking toward the future, the investigators reason that specific manipulation of the nuclear digestion by autophagy holds promise to intervene in age-related diseases.
The team showed that blocking a peptide, which inhibits LC3-laminB1 interaction, is able to slow cell aging. The implications are that a small molecule could be made to stop the long-term “strategic defeat” of the senescence pathway, and to treat age-related diseases, especially those related to chronic inflammation.
Such a molecule might also be able to ameliorate the side effects of chemotherapy or radiation therapy in cancer patients. Drs Dou and Berger are actively investigating this possibility. 
Image by Sarah Pfau
Autophagy works in the cell nucleus to guard against the start of cancer, according to research published in Nature.
The study showed, for the first time, that autophagy is used to digest nuclear material in mammalian cells.
“We found that the molecular machinery of autophagy guides the degradation of components of the nuclear lamina in mammals,” said study author Shelley Berger, PhD, of the University of Pennsylvania in Philadelphia.
The nuclear lamina is a network of protein filaments lining the inside of the membrane of the nucleus. It provides mechanical support to the nucleus and regulates gene expression by making some areas of the genome less or more available to be transcribed into messenger RNA.
Previous studies showed that the autophagy protein LC3 can be found in the nucleus, but it was not clear why, as the protein was thought to be functional in the cytoplasm. Study author Zhixun Dou, PhD, came to the Berger lab with this in mind.
At the same time, Peter Adams, PhD, from the University of Glasgow in Scotland, published a study on the breakdown of the nuclear lamina in which he observed a peculiar protrusion, or blebbing, of the nuclear envelope into the cytoplasm. These blebs contained DNA, nuclear lamina proteins, and chromatin.
This evidence led the Berger and Adams labs to work together to find out what was going on.
Using biochemical and sequencing methods, Dr Dou found that laminB1, a key component of the nuclear lamina, and LC3 were contacting each other in the same places on chromatin.
In fact, LC3 and laminB1 are physically bound to each other. LC3 directly interacts with lamin B1 and binds to lamin-associated domains on chromatin.
Autophagy in cancer and aging
The investigators found that, in response to cellular stress that can cause cancer, LC3, chromatin, and laminB1 migrate from the nucleus—via the nuclear blebs—into the cytoplasm and are eventually targeted for disposal.
This breakdown of laminB1 and other nuclear material leads to senescence. The Berger and Adams labs have been studying senescence in conjunction with cancer for quite some time. One way human cells protect themselves from becoming cancerous is to accelerate aging via senescence so the cells can no longer replicate.
The team showed that when a cell’s DNA is damaged or an oncogene is activated (both of which can cause cancer), a normal cell triggers the digestion of nuclear lamina by autophagy, which promotes senescence. Inhibiting this digestion of nuclear material weakens the senescence program and leads to cancerous growth of cells.
“The nucleus is the headquarters of a cell,” Dr Dou said. “When a cell receives a danger alarm, amazingly, it deliberately messes up its headquarters, with the consequence that many functions are completely stopped for the cell. Our study suggests this new function of autophagy is a guarding mechanism that protects cells from becoming cancerous.”
The investigators noted that senescence is associated with normal aging, and senescent cells accumulate in aged tissues, which impair the normal functions of the tissue and contribute to age-related diseases. While autophagy in the nucleus is able to restrain cancer, this machinery is improperly turned on during normal aging.
“There is a short-term ‘tactical’ advantage, but a long-term ‘strategic’ defeat,” Dr Berger explained. “This mechanism makes a normal cell, even without cancer stress, get old much faster, and in a detrimental way.”
In support of this notion, the investigators found that, in late-middle-aged normal cells, blocking the autophagy-driven breakdown of the nuclear lamina can make cells live 60% longer. In fact, the team said the age extension is equivalent to a 70-year-old person living to over 110 years old.
Looking toward the future, the investigators reason that specific manipulation of the nuclear digestion by autophagy holds promise to intervene in age-related diseases.
The team showed that blocking a peptide, which inhibits LC3-laminB1 interaction, is able to slow cell aging. The implications are that a small molecule could be made to stop the long-term “strategic defeat” of the senescence pathway, and to treat age-related diseases, especially those related to chronic inflammation.
Such a molecule might also be able to ameliorate the side effects of chemotherapy or radiation therapy in cancer patients. Drs Dou and Berger are actively investigating this possibility.
Image by Sarah Pfau
Autophagy works in the cell nucleus to guard against the start of cancer, according to research published in Nature.
The study showed, for the first time, that autophagy is used to digest nuclear material in mammalian cells.
“We found that the molecular machinery of autophagy guides the degradation of components of the nuclear lamina in mammals,” said study author Shelley Berger, PhD, of the University of Pennsylvania in Philadelphia.
The nuclear lamina is a network of protein filaments lining the inside of the membrane of the nucleus. It provides mechanical support to the nucleus and regulates gene expression by making some areas of the genome less or more available to be transcribed into messenger RNA.
Previous studies showed that the autophagy protein LC3 can be found in the nucleus, but it was not clear why, as the protein was thought to be functional in the cytoplasm. Study author Zhixun Dou, PhD, came to the Berger lab with this in mind.
At the same time, Peter Adams, PhD, from the University of Glasgow in Scotland, published a study on the breakdown of the nuclear lamina in which he observed a peculiar protrusion, or blebbing, of the nuclear envelope into the cytoplasm. These blebs contained DNA, nuclear lamina proteins, and chromatin.
This evidence led the Berger and Adams labs to work together to find out what was going on.
Using biochemical and sequencing methods, Dr Dou found that laminB1, a key component of the nuclear lamina, and LC3 were contacting each other in the same places on chromatin.
In fact, LC3 and laminB1 are physically bound to each other. LC3 directly interacts with lamin B1 and binds to lamin-associated domains on chromatin.
Autophagy in cancer and aging
The investigators found that, in response to cellular stress that can cause cancer, LC3, chromatin, and laminB1 migrate from the nucleus—via the nuclear blebs—into the cytoplasm and are eventually targeted for disposal.
This breakdown of laminB1 and other nuclear material leads to senescence. The Berger and Adams labs have been studying senescence in conjunction with cancer for quite some time. One way human cells protect themselves from becoming cancerous is to accelerate aging via senescence so the cells can no longer replicate.
The team showed that when a cell’s DNA is damaged or an oncogene is activated (both of which can cause cancer), a normal cell triggers the digestion of nuclear lamina by autophagy, which promotes senescence. Inhibiting this digestion of nuclear material weakens the senescence program and leads to cancerous growth of cells.
“The nucleus is the headquarters of a cell,” Dr Dou said. “When a cell receives a danger alarm, amazingly, it deliberately messes up its headquarters, with the consequence that many functions are completely stopped for the cell. Our study suggests this new function of autophagy is a guarding mechanism that protects cells from becoming cancerous.”
The investigators noted that senescence is associated with normal aging, and senescent cells accumulate in aged tissues, which impair the normal functions of the tissue and contribute to age-related diseases. While autophagy in the nucleus is able to restrain cancer, this machinery is improperly turned on during normal aging.
“There is a short-term ‘tactical’ advantage, but a long-term ‘strategic’ defeat,” Dr Berger explained. “This mechanism makes a normal cell, even without cancer stress, get old much faster, and in a detrimental way.”
In support of this notion, the investigators found that, in late-middle-aged normal cells, blocking the autophagy-driven breakdown of the nuclear lamina can make cells live 60% longer. In fact, the team said the age extension is equivalent to a 70-year-old person living to over 110 years old.
Looking toward the future, the investigators reason that specific manipulation of the nuclear digestion by autophagy holds promise to intervene in age-related diseases.
The team showed that blocking a peptide, which inhibits LC3-laminB1 interaction, is able to slow cell aging. The implications are that a small molecule could be made to stop the long-term “strategic defeat” of the senescence pathway, and to treat age-related diseases, especially those related to chronic inflammation.
Such a molecule might also be able to ameliorate the side effects of chemotherapy or radiation therapy in cancer patients. Drs Dou and Berger are actively investigating this possibility.