Page 37 - 2014 Printable Abstract Book
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vivo for many months post-irradiation. We can identify these events at the low fluences that occur in
space, wherein individual cells are at risk of a single traversal from a heavy ion, but generally not from two
or more heavy ions delivered simultaneously. Recently, our work has shown that loss of heterozygosity
on other non-selected chromosomes (genomic LOH) is another signature of exposure to energetic charged
particles. These non-selected events also are typically large, chromosomal scale events. They are rare in
non-mutant clones from the same irradiated tissues or cultures, and they are also rare in spontaneously
arising Aprt mutants, but they are found after low fluence exposure to heavy ions. We show that low
fluence exposure to heavy ions is both necessary and sufficient to establish genomic LOH in vitro or in
vivo, while for protons, the irradiated mouse is more permissive than cultured cells for the induction of
genomic LOH. Taken together, our studies indicate that low fluence exposure to charged particle radiation
produces signature mutations that are most often large, chromosomal scale events that persist in vivo for
extended periods of time.
(S304) Genetic co-regulation of genome surveillance and carcinogenesis. Howard B. Lieberman,
Columbia University, Center for Radiological Research, New York, NY
When cells incur DNA damage it is critical for proper repair to occur or deleterious consequences,
such as the development of genomic instability, mutation, and cancer or cell death might ensue. A variety
of proteins, most notably members of the evolutionarily conserved RAD9-HUS1-RAD1 (9-1-1)
heterotrimeric complex play a surveillance role, whereby these proteins scan the genome, recognize DNA
damage, and transduce signals to effector molecules that subsequently regulate the DNA damage
response. This cellular response to DNA involves DNA repair, cell cycle checkpoint control, and apoptotic
functions. When at least one of these proteins, RAD9, is present in aberrantly high or low levels cancer
can develop, even in the absence of exogenous DNA damaging agents. In addition, as shown for prostate
cancer cells, high levels of the protein are causally linked to phenotypes characteristic of metastatic
activities, such as rapid, extensive cell migration, anchorage-independent growth, and anoikis resistance.
What remains unclear are whether the same functions of RAD9 that participate in DNA damage
surveillance are also the ones involved in carcinogenic and metastatic processes. Clearly these activities
are co-regulated by proteins like RAD9, but the precise, respective molecular mechanisms involved have
yet to be elucidated.
S04 EPIGENETIC REPORGRAMMING IN THE RADIATION RESPONSE
The field of radiation epigenetics is rapidly expanding in the context of basic and clinical
radiobiology. The Sunday morning symposium “Epigenetic Reprogramming in the Radiation Response”
will highlight various aspects of these radiation-related changes with a focus on the importance of DNA
methylation and histone marks. Dr. Hendzel will open the session with a discussion of the importance and
complexity of polycomb protein histone modifications in modulation of radiation induced DNA damage
responses and carcinogenesis. Dr. Koturbash will follow with a talk on the effects of radiation exposure
on global, repetitive element-associated and gene-specific DNA methylation in bone marrow. Next, Dr.
Baulch will continue the discussion of DNA methylation with regards to the effects of high versus low LET
radiation exposures. The session will close with a lecture by Dr. Steven Zielske regarding the epigenetic
35 | P a g e
space, wherein individual cells are at risk of a single traversal from a heavy ion, but generally not from two
or more heavy ions delivered simultaneously. Recently, our work has shown that loss of heterozygosity
on other non-selected chromosomes (genomic LOH) is another signature of exposure to energetic charged
particles. These non-selected events also are typically large, chromosomal scale events. They are rare in
non-mutant clones from the same irradiated tissues or cultures, and they are also rare in spontaneously
arising Aprt mutants, but they are found after low fluence exposure to heavy ions. We show that low
fluence exposure to heavy ions is both necessary and sufficient to establish genomic LOH in vitro or in
vivo, while for protons, the irradiated mouse is more permissive than cultured cells for the induction of
genomic LOH. Taken together, our studies indicate that low fluence exposure to charged particle radiation
produces signature mutations that are most often large, chromosomal scale events that persist in vivo for
extended periods of time.
(S304) Genetic co-regulation of genome surveillance and carcinogenesis. Howard B. Lieberman,
Columbia University, Center for Radiological Research, New York, NY
When cells incur DNA damage it is critical for proper repair to occur or deleterious consequences,
such as the development of genomic instability, mutation, and cancer or cell death might ensue. A variety
of proteins, most notably members of the evolutionarily conserved RAD9-HUS1-RAD1 (9-1-1)
heterotrimeric complex play a surveillance role, whereby these proteins scan the genome, recognize DNA
damage, and transduce signals to effector molecules that subsequently regulate the DNA damage
response. This cellular response to DNA involves DNA repair, cell cycle checkpoint control, and apoptotic
functions. When at least one of these proteins, RAD9, is present in aberrantly high or low levels cancer
can develop, even in the absence of exogenous DNA damaging agents. In addition, as shown for prostate
cancer cells, high levels of the protein are causally linked to phenotypes characteristic of metastatic
activities, such as rapid, extensive cell migration, anchorage-independent growth, and anoikis resistance.
What remains unclear are whether the same functions of RAD9 that participate in DNA damage
surveillance are also the ones involved in carcinogenic and metastatic processes. Clearly these activities
are co-regulated by proteins like RAD9, but the precise, respective molecular mechanisms involved have
yet to be elucidated.
S04 EPIGENETIC REPORGRAMMING IN THE RADIATION RESPONSE
The field of radiation epigenetics is rapidly expanding in the context of basic and clinical
radiobiology. The Sunday morning symposium “Epigenetic Reprogramming in the Radiation Response”
will highlight various aspects of these radiation-related changes with a focus on the importance of DNA
methylation and histone marks. Dr. Hendzel will open the session with a discussion of the importance and
complexity of polycomb protein histone modifications in modulation of radiation induced DNA damage
responses and carcinogenesis. Dr. Koturbash will follow with a talk on the effects of radiation exposure
on global, repetitive element-associated and gene-specific DNA methylation in bone marrow. Next, Dr.
Baulch will continue the discussion of DNA methylation with regards to the effects of high versus low LET
radiation exposures. The session will close with a lecture by Dr. Steven Zielske regarding the epigenetic
35 | P a g e
