Abstract:Purpose
Clarify which DNA double strand break repair pathway, non-homologous end-joining (NHEJ), homologous recombination repair (HRR) or both, plays a key role in potentially lethal damage repair (PLDR).
Methods and materials
Combining published data and our new potentially lethal damage repair (PLDR) data, we explain whether similar to sublethal damage repair (SLDR), PLDR also mainly depends on NHEJ versus HRR. The PLDR data were used the same cell lines: wild type, HRR or NHEJ deficient fibroblast cells, … Show more
“…Brca1 is upregulated in response to genotoxic stress (De Siervi et al, 2010). A lack of change in expression of Brca1 in bank voles from the CEZ indicates that the homologous recombination repair pathway is not a key component of the response to environmental radionuclides, consistent with a recent study of expression of DBS repair pathways during exposure to IR (Liu et al, 2016). Arabidopsis from the CEZ show reduced recombination, which might prevent gross chromosomal rearrangements (Kovalchuk et al, 2014).…”
Exposure to ionizing radiation (IR) from radionuclides released into the environment can damage DNA. An expected response to exposure to environmental radionuclides, therefore, is initiation of DNA damage response (DDR) pathways. Increased DNA damage is a characteristic of many organisms exposed to radionuclides but expression of DDR genes of wildlife inhabiting an area contaminated by radionuclides is poorly understood. We quantified expression of five central DDR genes Atm, Mre11, p53, Brca1, and p21 in the livers of the bank vole Myodes glareolus that inhabited areas within the Chernobyl Exclusion Zone (CEZ) that differed in levels of ambient radioactivity, and also from control areas outside the CEZ (i.e., sites with no detectable environmental radionuclides) in Ukraine. Expression of these DDR genes did not significantly differ between male and female bank voles, nor among sites within the CEZ. We found a near two-fold upregulation in the DDR initiators Mre11 and Atm in animals collected from the CEZ compared with samples from control sites. As Atm is an important regulator of oxidative stress, our data suggest that antioxidant activity may be a key component of the defense against exposure to environmental radioactivity.
“…Brca1 is upregulated in response to genotoxic stress (De Siervi et al, 2010). A lack of change in expression of Brca1 in bank voles from the CEZ indicates that the homologous recombination repair pathway is not a key component of the response to environmental radionuclides, consistent with a recent study of expression of DBS repair pathways during exposure to IR (Liu et al, 2016). Arabidopsis from the CEZ show reduced recombination, which might prevent gross chromosomal rearrangements (Kovalchuk et al, 2014).…”
Exposure to ionizing radiation (IR) from radionuclides released into the environment can damage DNA. An expected response to exposure to environmental radionuclides, therefore, is initiation of DNA damage response (DDR) pathways. Increased DNA damage is a characteristic of many organisms exposed to radionuclides but expression of DDR genes of wildlife inhabiting an area contaminated by radionuclides is poorly understood. We quantified expression of five central DDR genes Atm, Mre11, p53, Brca1, and p21 in the livers of the bank vole Myodes glareolus that inhabited areas within the Chernobyl Exclusion Zone (CEZ) that differed in levels of ambient radioactivity, and also from control areas outside the CEZ (i.e., sites with no detectable environmental radionuclides) in Ukraine. Expression of these DDR genes did not significantly differ between male and female bank voles, nor among sites within the CEZ. We found a near two-fold upregulation in the DDR initiators Mre11 and Atm in animals collected from the CEZ compared with samples from control sites. As Atm is an important regulator of oxidative stress, our data suggest that antioxidant activity may be a key component of the defense against exposure to environmental radioactivity.
“…Further studies comparing different experimental set-ups could reveal additional phenomenological insights of the radiation response. For instance, by varying the time before re-plating after irradiation (delayed plating), the effect of ‘potentially lethal damage’ could be assessed (Ref 67 ). Fig.…”
FLASH radiotherapy is a novel technique that has been shown in numerous preclinical in vivo studies to have the potential to be the next important improvement in cancer treatment. However, the biological mechanisms responsible for the selective FLASH sparing effect of normal tissues are not yet known. An optimal translation of FLASH radiotherapy into the clinic would require a good understanding of the specific beam parameters that induces a FLASH effect, environmental conditions affecting the response, and the radiobiological mechanisms involved. Even though the FLASH effect has generally been considered as an in vivo effect, studies finding these answers would be difficult and ethically challenging to carry out solely in animals. Hence, suitable in vitro studies aimed towards finding these answers are needed. In this review, we describe and summarise several in vitro assays that have been used or could be used to finally elucidate the mechanisms behind the FLASH effect.
Highlights d The crystal structure of EPC1 bound to MBTD1 is determined d MBTD1 employs two distinct regions to recognize H4K20me and EPC1 d Mutations at the MBTD1-EPC1 interface affect gene expression and DNA repair
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