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The role of Drosophila mismatch repair in suppressing recombination between diverged sequences.

Do AT, LaRocque JR - Sci Rep (2015)

Bottom Line: DNA double-strand breaks (DSBs) must be accurately repaired to maintain genomic integrity.DSBs can be repaired by homologous recombination (HR), which uses an identical sequence as a template to restore the genetic information lost at the break.These findings suggest that MMR has an early role in suppressing recombination between diverged sequences that is conserved in Drosophila.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Science, Georgetown University Medical Center, Washington DC 20057.

ABSTRACT
DNA double-strand breaks (DSBs) must be accurately repaired to maintain genomic integrity. DSBs can be repaired by homologous recombination (HR), which uses an identical sequence as a template to restore the genetic information lost at the break. Suppression of recombination between diverged sequences is essential to the repair of DSBs without aberrant and potentially mutagenic recombination between non-identical sequences, such as Alu repeats in the human genome. The mismatch repair (MMR) machinery has been found to suppress recombination between diverged sequences in murine cells. To test if this phenomenon is conserved in whole organisms, two DSB repair systems were utilized in Drosophila melanogaster. The DR-white and DR-white.mu assays provide a method of measuring DSB repair outcomes between identical and diverged sequences respectively. msh6(-/-) flies, deficient in MMR, were not capable of suppressing recombination between sequences with 1.4% divergence, and the average gene conversion tract length did not differ between msh6(-/+) and msh6(-/-)flies. These findings suggest that MMR has an early role in suppressing recombination between diverged sequences that is conserved in Drosophila.

No MeSH data available.


Related in: MedlinePlus

Models of DSB repair.DSBs can be repaired by homologous recombination (HR), single-strand annealing (SSA) or non-homologous end joining (NHEJ). In NHEJ, processed ends are joined by ligation (star). HR repair is initiated by 5′ to 3′ resection at the DSB. If the DSB occurs between direct repeats (yellow boxes), extensive resection followed by annealing of the direct repeats results in SSA, resulting in loss of the intervening sequence. Alternatively, the resected 3′ overhang invades the homologous template (blue) to initiate repair synthesis (blue dotted line). The invaded strand may result in heteroduplex DNA between the red and blue sequences (hDNA, black box). DNA repair synthesis is then initiated. (A) In the DSBR model, the second strand of the DSB is captured, followed by repair synthesis, and then the newly synthesized strands are ligated to form a double Holliday junction (dHJ). Depending on how the dHJ is cleaved (arrow heads), resolution can result in a crossover or a noncrossover. (B) In SDSA, the newly synthesized strand dissociates, anneals to the other end, the gap is filled in, and nicks ligated to result in a noncrossover product. The newly synthesized strands in both DSBR and SDSA also form hDNA. hDNA in these products can be repaired by mismatch repair, resulting in gene conversion (not shown). Direct repeats are shown only for SSA for simplicity.
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f1: Models of DSB repair.DSBs can be repaired by homologous recombination (HR), single-strand annealing (SSA) or non-homologous end joining (NHEJ). In NHEJ, processed ends are joined by ligation (star). HR repair is initiated by 5′ to 3′ resection at the DSB. If the DSB occurs between direct repeats (yellow boxes), extensive resection followed by annealing of the direct repeats results in SSA, resulting in loss of the intervening sequence. Alternatively, the resected 3′ overhang invades the homologous template (blue) to initiate repair synthesis (blue dotted line). The invaded strand may result in heteroduplex DNA between the red and blue sequences (hDNA, black box). DNA repair synthesis is then initiated. (A) In the DSBR model, the second strand of the DSB is captured, followed by repair synthesis, and then the newly synthesized strands are ligated to form a double Holliday junction (dHJ). Depending on how the dHJ is cleaved (arrow heads), resolution can result in a crossover or a noncrossover. (B) In SDSA, the newly synthesized strand dissociates, anneals to the other end, the gap is filled in, and nicks ligated to result in a noncrossover product. The newly synthesized strands in both DSBR and SDSA also form hDNA. hDNA in these products can be repaired by mismatch repair, resulting in gene conversion (not shown). Direct repeats are shown only for SSA for simplicity.

Mentions: Maintaining genome integrity is essential for the survival of a cell and for accurate transmission of genetic information from generation to generation. One threat to the genome is DNA damage, which occurs from both exogenous and endogenous sources. A particularly deleterious type of DNA damage is the double-strand break (DSB), where both strands of the DNA double helix are broken. DSBs result from exogenous sources such as ionizing radiation, and endogenous cellular byproducts such as high-energy free radicals and single-strand breaks that are converted to DSBs during replication. DSBs can be repaired through homologous recombination (HR), non-homologous end-joining (NHEJ) or single-strand annealing (SSA)1 (Fig. 1). If not accurately repaired, DSBs can result in cell death, mutations, cancer, and premature aging2.


The role of Drosophila mismatch repair in suppressing recombination between diverged sequences.

Do AT, LaRocque JR - Sci Rep (2015)

Models of DSB repair.DSBs can be repaired by homologous recombination (HR), single-strand annealing (SSA) or non-homologous end joining (NHEJ). In NHEJ, processed ends are joined by ligation (star). HR repair is initiated by 5′ to 3′ resection at the DSB. If the DSB occurs between direct repeats (yellow boxes), extensive resection followed by annealing of the direct repeats results in SSA, resulting in loss of the intervening sequence. Alternatively, the resected 3′ overhang invades the homologous template (blue) to initiate repair synthesis (blue dotted line). The invaded strand may result in heteroduplex DNA between the red and blue sequences (hDNA, black box). DNA repair synthesis is then initiated. (A) In the DSBR model, the second strand of the DSB is captured, followed by repair synthesis, and then the newly synthesized strands are ligated to form a double Holliday junction (dHJ). Depending on how the dHJ is cleaved (arrow heads), resolution can result in a crossover or a noncrossover. (B) In SDSA, the newly synthesized strand dissociates, anneals to the other end, the gap is filled in, and nicks ligated to result in a noncrossover product. The newly synthesized strands in both DSBR and SDSA also form hDNA. hDNA in these products can be repaired by mismatch repair, resulting in gene conversion (not shown). Direct repeats are shown only for SSA for simplicity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663472&req=5

f1: Models of DSB repair.DSBs can be repaired by homologous recombination (HR), single-strand annealing (SSA) or non-homologous end joining (NHEJ). In NHEJ, processed ends are joined by ligation (star). HR repair is initiated by 5′ to 3′ resection at the DSB. If the DSB occurs between direct repeats (yellow boxes), extensive resection followed by annealing of the direct repeats results in SSA, resulting in loss of the intervening sequence. Alternatively, the resected 3′ overhang invades the homologous template (blue) to initiate repair synthesis (blue dotted line). The invaded strand may result in heteroduplex DNA between the red and blue sequences (hDNA, black box). DNA repair synthesis is then initiated. (A) In the DSBR model, the second strand of the DSB is captured, followed by repair synthesis, and then the newly synthesized strands are ligated to form a double Holliday junction (dHJ). Depending on how the dHJ is cleaved (arrow heads), resolution can result in a crossover or a noncrossover. (B) In SDSA, the newly synthesized strand dissociates, anneals to the other end, the gap is filled in, and nicks ligated to result in a noncrossover product. The newly synthesized strands in both DSBR and SDSA also form hDNA. hDNA in these products can be repaired by mismatch repair, resulting in gene conversion (not shown). Direct repeats are shown only for SSA for simplicity.
Mentions: Maintaining genome integrity is essential for the survival of a cell and for accurate transmission of genetic information from generation to generation. One threat to the genome is DNA damage, which occurs from both exogenous and endogenous sources. A particularly deleterious type of DNA damage is the double-strand break (DSB), where both strands of the DNA double helix are broken. DSBs result from exogenous sources such as ionizing radiation, and endogenous cellular byproducts such as high-energy free radicals and single-strand breaks that are converted to DSBs during replication. DSBs can be repaired through homologous recombination (HR), non-homologous end-joining (NHEJ) or single-strand annealing (SSA)1 (Fig. 1). If not accurately repaired, DSBs can result in cell death, mutations, cancer, and premature aging2.

Bottom Line: DNA double-strand breaks (DSBs) must be accurately repaired to maintain genomic integrity.DSBs can be repaired by homologous recombination (HR), which uses an identical sequence as a template to restore the genetic information lost at the break.These findings suggest that MMR has an early role in suppressing recombination between diverged sequences that is conserved in Drosophila.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Science, Georgetown University Medical Center, Washington DC 20057.

ABSTRACT
DNA double-strand breaks (DSBs) must be accurately repaired to maintain genomic integrity. DSBs can be repaired by homologous recombination (HR), which uses an identical sequence as a template to restore the genetic information lost at the break. Suppression of recombination between diverged sequences is essential to the repair of DSBs without aberrant and potentially mutagenic recombination between non-identical sequences, such as Alu repeats in the human genome. The mismatch repair (MMR) machinery has been found to suppress recombination between diverged sequences in murine cells. To test if this phenomenon is conserved in whole organisms, two DSB repair systems were utilized in Drosophila melanogaster. The DR-white and DR-white.mu assays provide a method of measuring DSB repair outcomes between identical and diverged sequences respectively. msh6(-/-) flies, deficient in MMR, were not capable of suppressing recombination between sequences with 1.4% divergence, and the average gene conversion tract length did not differ between msh6(-/+) and msh6(-/-)flies. These findings suggest that MMR has an early role in suppressing recombination between diverged sequences that is conserved in Drosophila.

No MeSH data available.


Related in: MedlinePlus