Mitochondria are energy-producing intracellular organelles containing their own genetic material in the form of mitochondrial DNA (mtDNA), which codes for proteins and RNAs essential for mitochondrial function. Some mtDNA mutations can cause mitochondria-related diseases. Mitochondrial diseases are a heterogeneous group of inherited disorders with no cure, in which mutated mtDNA is passed from mothers to offspring via maternal egg cytoplasm. Mitochondrial replacement (MR) is a genome transfer technology in which mtDNA carrying disease-related mutations is replaced by presumably disease-free mtDNA. This therapy aims at preventing the transmission of known disease-causing mitochondria to the next generation. Here, a proof of concept for the specific removal or editing of mtDNA disease-related mutations by genome editing is introduced. Although the amount of mtDNA carryover introduced into human oocytes during nuclear transfer is low, the safety of mtDNA heteroplasmy remains a concern. This is particularly true regarding donor-recipient mtDNA mismatch (mtDNA–mtDNA), mtDNA-nuclear DNA (nDNA) mismatch caused by mixing recipient nDNA with donor mtDNA, and mtDNA replicative segregation. These conditions can lead to mtDNA genetic drift and reversion to the original genotype. In this review, we address the current state of knowledge regarding nuclear transplantation for preventing the inheritance of mitochondrial diseases.
Mitochondria are essential for the normal functions of multicellular life. Human mitochondria contain a residual genome (mitochondrial DNA, mtDNA), which is critical for the functions of mitochondria in energy production through oxidative phosphorylation (OXPHOS), calcium and reactive oxygen species (ROS) signaling, and regulation of apoptosis. mtDNA is a double-stranded, circular molecule of 16 569 nucleotide pairs containing 37 genes encoding two rRNAs, 22 tRNAs, and 13 protein-coding sequences, which are distributed
Summary
Zygotic genome activation (ZGA) begins after fertilization and is essential for establishing pluripotency and genome stability. However, it is unclear how ZGA genes prevent mitotic errors. Here we show that knockout of the ZGA gene
Zscan5b
, which encodes a SCAN domain with C2H2 zinc fingers, causes a high incidence of chromosomal abnormalities in embryonic stem cells (ESCs), and leads to the development of early-stage cancers. After irradiation,
Zscan5b
-deficient ESCs displayed significantly increased levels of γ-H2AX despite increased expression of the DNA repair genes
Rad51l3
and
Bard
. Re-expression of
Zscan5b
reduced γ-H2AX content, implying a role for
Zscan5b
in DNA damage repair processes. A co-immunoprecipitation analysis showed that
Zscan5b
bound to the linker histone H1, suggesting that
Zscan5b
may protect chromosomal architecture. Our report demonstrates that the ZGA gene
Zscan5b
is involved in genomic integrity and acts to promote DNA damage repair and regulate chromatin dynamics during mitosis.
Endometrial cancer is one of the most common types of gynecologic cancer. The major prognostic factors of endometrial carcinoma include FIGO (International Federation of Gynecology & Obstetrics) staging, myometrial invasion, and histologic type and grade. 1Although total hysterectomy and bilateral salpingo-oophorectomy are the reference standard procedures for surgical staging, lymphadenectomy is required when the case is considered as high-risk for post-surgical recurrence.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.