Genetic variance modifies apoptosis susceptibility in mature oocytes via alterations in DNA repair capacity and mitochondrial ultrastructure

G. I. Perez; B. M. Acton; A. Jurisicova; G. A. Perkins; A. White; J. Brown; A. M. Trbovich; M. R. Kim; R. Fissore; J. Xu; A. Ahmady; S. G. D'Estaing; H. Li; W. Kagawa; H. Kurumizaka; S. Yokoyama; H. Okada; T. W. Mak; M. H. Ellisman; R. F. Casper; J. L. Tilly

doi:10.1038/sj.cdd.4402050

Genetic variance modifies apoptosis susceptibility in mature oocytes via alterations in DNA repair capacity and mitochondrial ultrastructure

G. I. Perez
, B. M. Acton
, A. Jurisicova
, G. A. Perkins
, A. White
, J. Brown
, A. M. Trbovich
, M. R. Kim
, R. Fissore
, J. Xu
, A. Ahmady
, S. G. D'Estaing
, H. Li
, W. Kagawa
, H. Kurumizaka
, S. Yokoyama
, H. Okada
, T. W. Mak
, M. H. Ellisman
, R. F. Casper

J. L. Tilly

Department of Obstetrics and Gynecology

Research output: Contribution to journal › Article › peer-review

53 Scopus citations

Abstract

Although the identification of specific genes that regulate apoptosis has been a topic of intense study, little is known of the role that background genetic variance plays in modulating cell death. Using germ cells from inbred mouse strains, we found that apoptosis in mature (metaphase II) oocytes is affected by genetic background through at least two different mechanisms. The first, manifested in AKR/J mice, results in genomic instability. This is reflected by numerous DNA double-strand breaks in freshly isolated oocytes, causing a high apoptosis susceptibility and impaired embryonic development following fertilization. Microinjection of Rad51 reduces DNA damage, suppresses apoptosis and improves embryonic development. The second, manifested in FVB mice, results in dramatic dimorphisms in mitochondrial ultrastructure. This is correlated with cytochrome c release and a high apoptosis susceptibility, the latter of which is suppressed by pyruvate treatment, Smac/DIABLO deficiency, or microinjection of 'normal' mitochondria. Therefore, background genetic variance can profoundly affect apoptosis in female germ cells by disrupting both genomic DNA and mitochondrial integrity.

Original language	English
Pages (from-to)	524-533
Number of pages	10
Journal	Cell Death and Differentiation
Volume	14
Issue number	3
DOIs	https://doi.org/10.1038/sj.cdd.4402050
State	Published - Mar 2007

Bibliographical note

Funding Information:
Acknowledgements. We thank X Wang for recombinant Smac/DIABLO, M Gertsenstein for technical assistance, J Wrana and M Barrios-Rodiles for use of the luminometer, R Lawrence for assistance with the TxBR package and S Riley for assistance with figures. This work was supported by the National Institutes of Health (R01/R37-AG012279 to JLT; RR04050 to MHE), Vincent Memorial Research Funds (to JLT), the Harvard Center of Excellence on Women’s Health (to GIP), Michigan State University (to GIP) and the Canadian Institutes of Health Research (MOP-14058 to RFC and AJ; Doctoral Research Award to BMA).

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Perez, G. I., Acton, B. M., Jurisicova, A., Perkins, G. A., White, A., Brown, J., Trbovich, A. M., Kim, M. R., Fissore, R., Xu, J., Ahmady, A., D'Estaing, S. G., Li, H., Kagawa, W., Kurumizaka, H., Yokoyama, S., Okada, H., Mak, T. W., Ellisman, M. H., ... Tilly, J. L. (2007). Genetic variance modifies apoptosis susceptibility in mature oocytes via alterations in DNA repair capacity and mitochondrial ultrastructure. Cell Death and Differentiation, 14(3), 524-533. https://doi.org/10.1038/sj.cdd.4402050

@article{5cffc938459c4ae4847cef99abb0b391,

title = "Genetic variance modifies apoptosis susceptibility in mature oocytes via alterations in DNA repair capacity and mitochondrial ultrastructure",

abstract = "Although the identification of specific genes that regulate apoptosis has been a topic of intense study, little is known of the role that background genetic variance plays in modulating cell death. Using germ cells from inbred mouse strains, we found that apoptosis in mature (metaphase II) oocytes is affected by genetic background through at least two different mechanisms. The first, manifested in AKR/J mice, results in genomic instability. This is reflected by numerous DNA double-strand breaks in freshly isolated oocytes, causing a high apoptosis susceptibility and impaired embryonic development following fertilization. Microinjection of Rad51 reduces DNA damage, suppresses apoptosis and improves embryonic development. The second, manifested in FVB mice, results in dramatic dimorphisms in mitochondrial ultrastructure. This is correlated with cytochrome c release and a high apoptosis susceptibility, the latter of which is suppressed by pyruvate treatment, Smac/DIABLO deficiency, or microinjection of 'normal' mitochondria. Therefore, background genetic variance can profoundly affect apoptosis in female germ cells by disrupting both genomic DNA and mitochondrial integrity.",

author = "Perez, \{G. I.\} and Acton, \{B. M.\} and A. Jurisicova and Perkins, \{G. A.\} and A. White and J. Brown and Trbovich, \{A. M.\} and Kim, \{M. R.\} and R. Fissore and J. Xu and A. Ahmady and D'Estaing, \{S. G.\} and H. Li and W. Kagawa and H. Kurumizaka and S. Yokoyama and H. Okada and Mak, \{T. W.\} and Ellisman, \{M. H.\} and Casper, \{R. F.\} and Tilly, \{J. L.\}",

note = "Funding Information: Acknowledgements. We thank X Wang for recombinant Smac/DIABLO, M Gertsenstein for technical assistance, J Wrana and M Barrios-Rodiles for use of the luminometer, R Lawrence for assistance with the TxBR package and S Riley for assistance with figures. This work was supported by the National Institutes of Health (R01/R37-AG012279 to JLT; RR04050 to MHE), Vincent Memorial Research Funds (to JLT), the Harvard Center of Excellence on Women{\textquoteright}s Health (to GIP), Michigan State University (to GIP) and the Canadian Institutes of Health Research (MOP-14058 to RFC and AJ; Doctoral Research Award to BMA).",

year = "2007",

month = mar,

doi = "10.1038/sj.cdd.4402050",

language = "English",

volume = "14",

pages = "524--533",

journal = "Cell Death and Differentiation",

issn = "1350-9047",

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Perez, GI, Acton, BM, Jurisicova, A, Perkins, GA, White, A, Brown, J, Trbovich, AM, Kim, MR, Fissore, R, Xu, J, Ahmady, A, D'Estaing, SG, Li, H, Kagawa, W, Kurumizaka, H, Yokoyama, S, Okada, H, Mak, TW, Ellisman, MH, Casper, RF & Tilly, JL 2007, 'Genetic variance modifies apoptosis susceptibility in mature oocytes via alterations in DNA repair capacity and mitochondrial ultrastructure', Cell Death and Differentiation, vol. 14, no. 3, pp. 524-533. https://doi.org/10.1038/sj.cdd.4402050

TY - JOUR

T1 - Genetic variance modifies apoptosis susceptibility in mature oocytes via alterations in DNA repair capacity and mitochondrial ultrastructure

AU - Perez, G. I.

AU - Acton, B. M.

AU - Jurisicova, A.

AU - Perkins, G. A.

AU - White, A.

AU - Brown, J.

AU - Trbovich, A. M.

AU - Kim, M. R.

AU - Fissore, R.

AU - Xu, J.

AU - Ahmady, A.

AU - D'Estaing, S. G.

AU - Li, H.

AU - Kagawa, W.

AU - Kurumizaka, H.

AU - Yokoyama, S.

AU - Okada, H.

AU - Mak, T. W.

AU - Ellisman, M. H.

AU - Casper, R. F.

AU - Tilly, J. L.

N1 - Funding Information: Acknowledgements. We thank X Wang for recombinant Smac/DIABLO, M Gertsenstein for technical assistance, J Wrana and M Barrios-Rodiles for use of the luminometer, R Lawrence for assistance with the TxBR package and S Riley for assistance with figures. This work was supported by the National Institutes of Health (R01/R37-AG012279 to JLT; RR04050 to MHE), Vincent Memorial Research Funds (to JLT), the Harvard Center of Excellence on Women’s Health (to GIP), Michigan State University (to GIP) and the Canadian Institutes of Health Research (MOP-14058 to RFC and AJ; Doctoral Research Award to BMA).

PY - 2007/3

Y1 - 2007/3

N2 - Although the identification of specific genes that regulate apoptosis has been a topic of intense study, little is known of the role that background genetic variance plays in modulating cell death. Using germ cells from inbred mouse strains, we found that apoptosis in mature (metaphase II) oocytes is affected by genetic background through at least two different mechanisms. The first, manifested in AKR/J mice, results in genomic instability. This is reflected by numerous DNA double-strand breaks in freshly isolated oocytes, causing a high apoptosis susceptibility and impaired embryonic development following fertilization. Microinjection of Rad51 reduces DNA damage, suppresses apoptosis and improves embryonic development. The second, manifested in FVB mice, results in dramatic dimorphisms in mitochondrial ultrastructure. This is correlated with cytochrome c release and a high apoptosis susceptibility, the latter of which is suppressed by pyruvate treatment, Smac/DIABLO deficiency, or microinjection of 'normal' mitochondria. Therefore, background genetic variance can profoundly affect apoptosis in female germ cells by disrupting both genomic DNA and mitochondrial integrity.

AB - Although the identification of specific genes that regulate apoptosis has been a topic of intense study, little is known of the role that background genetic variance plays in modulating cell death. Using germ cells from inbred mouse strains, we found that apoptosis in mature (metaphase II) oocytes is affected by genetic background through at least two different mechanisms. The first, manifested in AKR/J mice, results in genomic instability. This is reflected by numerous DNA double-strand breaks in freshly isolated oocytes, causing a high apoptosis susceptibility and impaired embryonic development following fertilization. Microinjection of Rad51 reduces DNA damage, suppresses apoptosis and improves embryonic development. The second, manifested in FVB mice, results in dramatic dimorphisms in mitochondrial ultrastructure. This is correlated with cytochrome c release and a high apoptosis susceptibility, the latter of which is suppressed by pyruvate treatment, Smac/DIABLO deficiency, or microinjection of 'normal' mitochondria. Therefore, background genetic variance can profoundly affect apoptosis in female germ cells by disrupting both genomic DNA and mitochondrial integrity.

UR - https://www.scopus.com/pages/publications/33847031240

U2 - 10.1038/sj.cdd.4402050

DO - 10.1038/sj.cdd.4402050

M3 - Article

C2 - 17039249

AN - SCOPUS:33847031240

SN - 1350-9047

VL - 14

SP - 524

EP - 533

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

IS - 3

ER -

Genetic variance modifies apoptosis susceptibility in mature oocytes via alterations in DNA repair capacity and mitochondrial ultrastructure

Abstract

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