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A model for the control of DNA integrity by the sperm nuclear matrix.

Gawecka JE, Ribas-Maynou J, Benet J, Ward WS - Asian J. Androl. (2015 Jul-Aug)

Bottom Line: The highly condensed chromatin of mammalian spermatozoa is usually considered to be biologically inert before fertilization.This suggests that a mechanism exists to monitor the health of spermatozoa during transit through the male reproductive tract and to destroy the genome of defective sperm cells.The site of DNA damage in SCF, the matrix attachment sites, are the same that we hypothesize initiate DNA synthesis in the zygote.

View Article: PubMed Central - PubMed

Affiliation: Institute for Biogenesis Research, Department of Anatomy, Biochemistry and Physiology; Department of Obstetrics, Gynecology and Women's Health, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96822, USA.

ABSTRACT
The highly condensed chromatin of mammalian spermatozoa is usually considered to be biologically inert before fertilization. However, we have demonstrated that even in this compacted state, sperm chromatin is subject to degradation at open configurations associated with the nuclear matrix through a process we have termed sperm chromatin fragmentation (SCF). This suggests that a mechanism exists to monitor the health of spermatozoa during transit through the male reproductive tract and to destroy the genome of defective sperm cells. The site of DNA damage in SCF, the matrix attachment sites, are the same that we hypothesize initiate DNA synthesis in the zygote. When sperm that have damaged DNA are injected into the oocyte, the newly created zygote responds by delaying DNA synthesis in the male pronucleus and, if the damage is severe enough, arresting the embryo's development. Here we present a model for paternal DNA regulation by the nuclear matrix that begins during sperm maturation and continues through early embryonic development.

No MeSH data available.


Related in: MedlinePlus

A Model for the nuclear matrix as a regulator for the paternal genome. (a) In normal sperm chromatin most of the DNA is protected by protamines that condense the DNA into tightly compacted toroids. Nuclease sensitive “toroid linkers” connect the toroids to each other, and these are bound to the nuclear matrix. (b) When SCF is induced by treating the sperm with divalent cations, double-stranded DNA breaks are induced at all matrix attachment sites, and the DNA remains bound to the matrix. At this stage, the DNA can still be reversed with EDTA. Zygotes created by injecting sperm at this stage into oocytes can support DNA replication with no evidence for DNA replication delays, but they do not develop to the blastocyst stage. (c) As SCF progresses, the breaks are no longer associated with the nuclear matrix. Zygotes created with these sperm have severe replication and developmental delays. (d) We hypothesize that this signaling mechanism helps the zygote repair minor DNA damage by slowing DNA replication at damaged sites to allow for repair.
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Figure 2: A Model for the nuclear matrix as a regulator for the paternal genome. (a) In normal sperm chromatin most of the DNA is protected by protamines that condense the DNA into tightly compacted toroids. Nuclease sensitive “toroid linkers” connect the toroids to each other, and these are bound to the nuclear matrix. (b) When SCF is induced by treating the sperm with divalent cations, double-stranded DNA breaks are induced at all matrix attachment sites, and the DNA remains bound to the matrix. At this stage, the DNA can still be reversed with EDTA. Zygotes created by injecting sperm at this stage into oocytes can support DNA replication with no evidence for DNA replication delays, but they do not develop to the blastocyst stage. (c) As SCF progresses, the breaks are no longer associated with the nuclear matrix. Zygotes created with these sperm have severe replication and developmental delays. (d) We hypothesize that this signaling mechanism helps the zygote repair minor DNA damage by slowing DNA replication at damaged sites to allow for repair.

Mentions: In this model, the sperm nuclear matrix functions to regulate aspects of the paternal genome related to chromatin integrity. As mentioned above, we propose that SCF functions to deactivate the paternal genome in defective spermatozoa during maturation. There are two factors involved, one in the surrounding fluid and the other the components of the sperm nuclear matrix at the sites of DNA attachment. We have previously suggested that a similar type of chromatin surveillance might function to eliminate sperm that are damaged or infected with pathogens during fertilization.62 SCF, however, is the most severe form of sperm chromatin degradation, and is probably activated only upon sperm death. Even though embryos injected with SCF-induced sperm do eventually progress through the first cell cycle, they do not develop to the blastocyst stage in vitro.46 Therefore, it is not likely that SCF as we have described it is directly related to normal physiological function after fertilization. Our data indicate that when SCF is activated genome-wide, embryos that are injected with the DNA-damaged sperm exhibit some delay of paternal DNA replication initiation in the pronuclei, suggesting that there is a mechanism that halts replication forks in the presence of double-stranded breaks at or near the MARs. This suggests that the same mechanism that deactivates the genome in sperm cell death also signals a zygotic response to the DNA damage. We propose that when a limited number of double-stranded breaks occur in the sperm genome below a certain threshold during spermiogenesis or fertilization due to mechanical stress, the nuclear matrix mediated double-strand breaks are activated at these loci only Figure 2. It is possible, for example, that when spermatozoa undergo single-stranded breaks from exposure to reactive oxygen species (ROS) that the OGG1 repair mechanism also signals the nuclear matrix to induce double-stranded breaks to slow DNA replication enough to allow the DNA to be repaired. After fertilization, these breaks might be repaired following replication delay. Somatic cells have a DNA damage tolerance (DDT) mechanism that allows DNA replication to continue in the presence of double-strand DNA breaks so that the entire cell cycle is not stalled.6364 We would not expect DDT to be activated in zygotes because this might propagate mutations in the template genome of the embryo. Rather, we would expect the DNA to be repaired.65


A model for the control of DNA integrity by the sperm nuclear matrix.

Gawecka JE, Ribas-Maynou J, Benet J, Ward WS - Asian J. Androl. (2015 Jul-Aug)

A Model for the nuclear matrix as a regulator for the paternal genome. (a) In normal sperm chromatin most of the DNA is protected by protamines that condense the DNA into tightly compacted toroids. Nuclease sensitive “toroid linkers” connect the toroids to each other, and these are bound to the nuclear matrix. (b) When SCF is induced by treating the sperm with divalent cations, double-stranded DNA breaks are induced at all matrix attachment sites, and the DNA remains bound to the matrix. At this stage, the DNA can still be reversed with EDTA. Zygotes created by injecting sperm at this stage into oocytes can support DNA replication with no evidence for DNA replication delays, but they do not develop to the blastocyst stage. (c) As SCF progresses, the breaks are no longer associated with the nuclear matrix. Zygotes created with these sperm have severe replication and developmental delays. (d) We hypothesize that this signaling mechanism helps the zygote repair minor DNA damage by slowing DNA replication at damaged sites to allow for repair.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492052&req=5

Figure 2: A Model for the nuclear matrix as a regulator for the paternal genome. (a) In normal sperm chromatin most of the DNA is protected by protamines that condense the DNA into tightly compacted toroids. Nuclease sensitive “toroid linkers” connect the toroids to each other, and these are bound to the nuclear matrix. (b) When SCF is induced by treating the sperm with divalent cations, double-stranded DNA breaks are induced at all matrix attachment sites, and the DNA remains bound to the matrix. At this stage, the DNA can still be reversed with EDTA. Zygotes created by injecting sperm at this stage into oocytes can support DNA replication with no evidence for DNA replication delays, but they do not develop to the blastocyst stage. (c) As SCF progresses, the breaks are no longer associated with the nuclear matrix. Zygotes created with these sperm have severe replication and developmental delays. (d) We hypothesize that this signaling mechanism helps the zygote repair minor DNA damage by slowing DNA replication at damaged sites to allow for repair.
Mentions: In this model, the sperm nuclear matrix functions to regulate aspects of the paternal genome related to chromatin integrity. As mentioned above, we propose that SCF functions to deactivate the paternal genome in defective spermatozoa during maturation. There are two factors involved, one in the surrounding fluid and the other the components of the sperm nuclear matrix at the sites of DNA attachment. We have previously suggested that a similar type of chromatin surveillance might function to eliminate sperm that are damaged or infected with pathogens during fertilization.62 SCF, however, is the most severe form of sperm chromatin degradation, and is probably activated only upon sperm death. Even though embryos injected with SCF-induced sperm do eventually progress through the first cell cycle, they do not develop to the blastocyst stage in vitro.46 Therefore, it is not likely that SCF as we have described it is directly related to normal physiological function after fertilization. Our data indicate that when SCF is activated genome-wide, embryos that are injected with the DNA-damaged sperm exhibit some delay of paternal DNA replication initiation in the pronuclei, suggesting that there is a mechanism that halts replication forks in the presence of double-stranded breaks at or near the MARs. This suggests that the same mechanism that deactivates the genome in sperm cell death also signals a zygotic response to the DNA damage. We propose that when a limited number of double-stranded breaks occur in the sperm genome below a certain threshold during spermiogenesis or fertilization due to mechanical stress, the nuclear matrix mediated double-strand breaks are activated at these loci only Figure 2. It is possible, for example, that when spermatozoa undergo single-stranded breaks from exposure to reactive oxygen species (ROS) that the OGG1 repair mechanism also signals the nuclear matrix to induce double-stranded breaks to slow DNA replication enough to allow the DNA to be repaired. After fertilization, these breaks might be repaired following replication delay. Somatic cells have a DNA damage tolerance (DDT) mechanism that allows DNA replication to continue in the presence of double-strand DNA breaks so that the entire cell cycle is not stalled.6364 We would not expect DDT to be activated in zygotes because this might propagate mutations in the template genome of the embryo. Rather, we would expect the DNA to be repaired.65

Bottom Line: The highly condensed chromatin of mammalian spermatozoa is usually considered to be biologically inert before fertilization.This suggests that a mechanism exists to monitor the health of spermatozoa during transit through the male reproductive tract and to destroy the genome of defective sperm cells.The site of DNA damage in SCF, the matrix attachment sites, are the same that we hypothesize initiate DNA synthesis in the zygote.

View Article: PubMed Central - PubMed

Affiliation: Institute for Biogenesis Research, Department of Anatomy, Biochemistry and Physiology; Department of Obstetrics, Gynecology and Women's Health, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96822, USA.

ABSTRACT
The highly condensed chromatin of mammalian spermatozoa is usually considered to be biologically inert before fertilization. However, we have demonstrated that even in this compacted state, sperm chromatin is subject to degradation at open configurations associated with the nuclear matrix through a process we have termed sperm chromatin fragmentation (SCF). This suggests that a mechanism exists to monitor the health of spermatozoa during transit through the male reproductive tract and to destroy the genome of defective sperm cells. The site of DNA damage in SCF, the matrix attachment sites, are the same that we hypothesize initiate DNA synthesis in the zygote. When sperm that have damaged DNA are injected into the oocyte, the newly created zygote responds by delaying DNA synthesis in the male pronucleus and, if the damage is severe enough, arresting the embryo's development. Here we present a model for paternal DNA regulation by the nuclear matrix that begins during sperm maturation and continues through early embryonic development.

No MeSH data available.


Related in: MedlinePlus