DNA repair gene mutations may explain declining ovarian reserve

February 17, 2013Carole No Comments »

Poor DNA repair may be the key to both cancer and egg aging, according to a new study.  “I think we have found a general theory of reproductive aging,” said Kutluk Oktay, a fertility specialist at New York Medical College and co-author of  “Impairment of BRCA1-Related DNA Double-Strand Break Repair Leads to Ovarian Aging in Mice and Humans”. Oktay’s research supports the idea that eggs decline and die with advancing maternal age because the genes responsible for repairing routine DNA strand breaks become less efficient or broken with age.

BRCA genes are known as tumor suppressor genes because they produce proteins which routinely repair broken strands of DNA.   If the BRCA genes have harmful mutations, they are unable to efficiently produce these DNA repair proteins, setting the stage for cell cancer. In eggs, the failure of these same DNA repair mechanisms appear to result in egg cell suicide or atretic eggs.

Oktay’s study looked at the reproductive effects of BRCA mutations and found these mutations were correlated with lower numbers of normal eggs in both women and mice. Under or over-expressing these DNA repair pathways by manipulating BRCA gene expression was able to degrade or improve egg’s ability to withstand exposure to mutagens in mice, raising the possibility that manipulating these pathways may give rise to future methods to protect ovarian reserve.

Ovarian reserve, the number of eggs within the ovary, was lower in women who had mutations in the BRCA1 and BRCA2 genes. Mice with these mutations had smaller litters than wildtype mice. Although women with BRCA2 mutations appear reproductively normal, there may be subtle effects accelerating the decline of oocytes that become more obvious at the end of the reproductive life span. In other words, these mutations may shorten the reproductive life span by accelerating the decline of the ovarian reserve, making reproduction later in life more difficult.

As women age, their ovarian reserve decreases. The natural decline in DNA repair mechanisms which accompanies aging may explain why fewer genetically normal eggs are available to older women. These observations can now be explained by disruption of a specific DNA repair pathway mediated by BRCA genes.

© 2013, Carole. All rights reserved.

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