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Credit: Eric Smith
Researchers say they’ve discovered how histones control PARP1’s ability to activate genes and repair DNA damage.
Their findings, published in Molecular Cell, appear to have implications for cancer treatment.
Specifically, the investigators found that chemical modification of the histone H2Av leads to substantial changes in nucleosome shape.
As a consequence, a previously hidden portion of the nucleosome becomes exposed and activates PARP1.
Upon activation, PARP1 assembles long branching molecules of Poly(ADP-ribose), which appear to open the DNA packaging around the site of PARP1 activation, thereby exposing specific genes for activation.
“[T]he nucleosome is often portrayed as a stable, inert structure, or a tiny ball,” said study author Alexei V. Tulin, PhD, of Fox Chase Cancer Center in Philadelphia.
“We found that the nucleosome is actually a quite dynamic structure. When we modified one histone, we changed the whole nucleosome.”
In addition to revealing new information about how histones control gene activation, Dr Tulin’s research elucidated a new mechanism of PARP1 regulation.
“This mechanism of PARP1 regulation by histones is still very new,” Dr Tulin said. “People believe that PARP1 is mainly activated through interactions with DNA, but we have found that the main pathway of PARP1 activation is through interactions with the nucleosome.”
Previous research suggested that combining standard anticancer agents with drugs that inhibit PARP1 can more effectively kill cancer cells. But clinical trials testing PARP1 inhibitors in cancer patients have produced disappointing results.
“I believe that, to a large extent, the previous setbacks were caused by a general misconception of the role of PARP1 in living cells and the mechanisms of PARP1 regulation,” Dr Tulin said. “Now that we know this mechanism of PARP1 regulation, we can design approaches to inhibit this protein in an effective way to better treat cancer.”
Dr Tulin and his colleagues are now developing the next generation of PARP1 inhibitors. Designed to block the newly identified mechanism of PARP1 activation, these inhibitors will specifically target PARP1, in contrast to the PARP1 inhibitors currently being tested in clinical trials. 
Credit: Eric Smith
Researchers say they’ve discovered how histones control PARP1’s ability to activate genes and repair DNA damage.
Their findings, published in Molecular Cell, appear to have implications for cancer treatment.
Specifically, the investigators found that chemical modification of the histone H2Av leads to substantial changes in nucleosome shape.
As a consequence, a previously hidden portion of the nucleosome becomes exposed and activates PARP1.
Upon activation, PARP1 assembles long branching molecules of Poly(ADP-ribose), which appear to open the DNA packaging around the site of PARP1 activation, thereby exposing specific genes for activation.
“[T]he nucleosome is often portrayed as a stable, inert structure, or a tiny ball,” said study author Alexei V. Tulin, PhD, of Fox Chase Cancer Center in Philadelphia.
“We found that the nucleosome is actually a quite dynamic structure. When we modified one histone, we changed the whole nucleosome.”
In addition to revealing new information about how histones control gene activation, Dr Tulin’s research elucidated a new mechanism of PARP1 regulation.
“This mechanism of PARP1 regulation by histones is still very new,” Dr Tulin said. “People believe that PARP1 is mainly activated through interactions with DNA, but we have found that the main pathway of PARP1 activation is through interactions with the nucleosome.”
Previous research suggested that combining standard anticancer agents with drugs that inhibit PARP1 can more effectively kill cancer cells. But clinical trials testing PARP1 inhibitors in cancer patients have produced disappointing results.
“I believe that, to a large extent, the previous setbacks were caused by a general misconception of the role of PARP1 in living cells and the mechanisms of PARP1 regulation,” Dr Tulin said. “Now that we know this mechanism of PARP1 regulation, we can design approaches to inhibit this protein in an effective way to better treat cancer.”
Dr Tulin and his colleagues are now developing the next generation of PARP1 inhibitors. Designed to block the newly identified mechanism of PARP1 activation, these inhibitors will specifically target PARP1, in contrast to the PARP1 inhibitors currently being tested in clinical trials.
Credit: Eric Smith
Researchers say they’ve discovered how histones control PARP1’s ability to activate genes and repair DNA damage.
Their findings, published in Molecular Cell, appear to have implications for cancer treatment.
Specifically, the investigators found that chemical modification of the histone H2Av leads to substantial changes in nucleosome shape.
As a consequence, a previously hidden portion of the nucleosome becomes exposed and activates PARP1.
Upon activation, PARP1 assembles long branching molecules of Poly(ADP-ribose), which appear to open the DNA packaging around the site of PARP1 activation, thereby exposing specific genes for activation.
“[T]he nucleosome is often portrayed as a stable, inert structure, or a tiny ball,” said study author Alexei V. Tulin, PhD, of Fox Chase Cancer Center in Philadelphia.
“We found that the nucleosome is actually a quite dynamic structure. When we modified one histone, we changed the whole nucleosome.”
In addition to revealing new information about how histones control gene activation, Dr Tulin’s research elucidated a new mechanism of PARP1 regulation.
“This mechanism of PARP1 regulation by histones is still very new,” Dr Tulin said. “People believe that PARP1 is mainly activated through interactions with DNA, but we have found that the main pathway of PARP1 activation is through interactions with the nucleosome.”
Previous research suggested that combining standard anticancer agents with drugs that inhibit PARP1 can more effectively kill cancer cells. But clinical trials testing PARP1 inhibitors in cancer patients have produced disappointing results.
“I believe that, to a large extent, the previous setbacks were caused by a general misconception of the role of PARP1 in living cells and the mechanisms of PARP1 regulation,” Dr Tulin said. “Now that we know this mechanism of PARP1 regulation, we can design approaches to inhibit this protein in an effective way to better treat cancer.”
Dr Tulin and his colleagues are now developing the next generation of PARP1 inhibitors. Designed to block the newly identified mechanism of PARP1 activation, these inhibitors will specifically target PARP1, in contrast to the PARP1 inhibitors currently being tested in clinical trials.