Impact of alternative DNA structures on DNA damage, DNA repair, and genetic instability

Abstract

Repetitive genomic sequences can adopt a number of alternative DNA structures that differ from the canonical B-form duplex (i.e. non-B DNA). These non-B DNA-forming sequences have been shown to have many important biological functions related to DNA metabolic processes; for example, they may have regulatory roles in DNA transcription and replication. In addition to these regulatory functions, non-B DNA can stimulate genetic instability in the presence or absence of DNA damage, via replication-dependent and/or replication-independent pathways. This review focuses on the interactions of non-B DNA conformations with DNA repair proteins and how these interactions impact genetic instability.

FANCJ suppresses microsatellite instability and lymphomagenesis independent of the Fanconi anemia pathway

“…Current models propose that expansions or contractions of repetitive sequences arise as a result of strand slippage during DNA polymerization, which is favored by the propensity of microsatellites to form DNA secondary structures within ssDNA that stabilize strand misalignments (Wang and Vasquez 2014). Indeed, the enhanced MSI observed following treatment with replication inhibitors in Fancj-deficient cells could be explained by the fact that this increases the presence of ssDNA at the replication fork, which favors DNA secondary structure formation.…”

Correlation between sperm ultrastructure in infertile patients with abnormal sperm morphology and DNA damage

“…DNA damage in sperm can be caused by multiple factors, including environmental pollution, diseases, poor lifestyle choices, microelements, and chemical and physical factors (Gong et al, 2014;Wang and Vasquez, 2014). The premise exists that sperm that possess excellent mobility must also have a well-behaved cell nucleus and organelles to provide enough materials and energy.…”

Trinucleotide Repeat Instability is Modulated by DNA Base Lesions and DNA Base Excision Repair

“…The TNR instability via DNA replication has been the most studied pathway of TNR instability, however, TNR instability has more recently been found to occur in nondividing somatic cells, indicating a role for other DNA metabolic processes (114,117,118). The TNR instability has since been found to result from any DNA metabolic process that creates regions of ssDNA, including DNA replication (119,120), repair (46,95), recombination (102), and gene transcription (121), due to the ability of ssDNA to form non-B form secondary structures.…”

“…DNA secondary structures can also be hotspots for the formation of further DNA damage as they expose ssDNA regions to DNA damaging agents. They can further cause remodeling the chromatin structure, which also makes the DNA more accessible to damaging agents and leads to further damage (114).…”

“…TNR instability results from the formation of DNA secondary structures such as hairpins, triplexes, quadruplexes, and sticky DNA (102,105,114), which form during DNA replication, repair, and recombination, and gene transcription (89,101,102,108). Base excision repair (BER) within TNR tracts has been linked to repeat instability (46,117), which results from a loss of coordination between key BER proteins and cofactors (46,67,105,111,117,147).…”