Deoxyribonucleic Acid Damage and Repair: Capitalizing on Our Understanding of the Mechanisms of Maintaining Genomic Integrity for Therapeutic Purposes

Abstract

Deoxyribonucleic acid (DNA) is the self-replicating hereditary material that provides a blueprint which, in collaboration with environmental influences, produces a structural and functional phenotype. As DNA coordinates and directs differentiation, growth, survival, and reproduction, it is responsible for life and the continuation of our species. Genome integrity requires the maintenance of DNA stability for the correct preservation of genetic information. This is facilitated by accurate DNA replication and precise DNA repair. DNA damage may arise from a wide range of both endogenous and exogenous sources but may be repaired through highly specific mechanisms. The most common mechanisms include mismatch, base excision, nucleotide excision, and double-strand DNA (dsDNA) break repair. Concurrent with regulation of the cell cycle, these mechanisms are precisely executed to ensure full restoration of damaged DNA. Failure or inaccuracy in DNA repair contributes to genome instability and loss of genetic information which may lead to mutations resulting in disease or loss of life. A detailed understanding of the mechanisms of DNA damage and its repair provides insight into disease pathogeneses and may facilitate diagnosis and the development of targeted therapies.

C1q/TNF‐related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastoma

“…Major DNA adducts generated by TMZ are N 7methylguanine (N 7 -MeG; 60-80%), N 3 -methyladenine (N 3 -MeA; 10-20%), and O 6 -methylguanine (O 6 -MeG; 5-10%) (Bobola et al, 2012). Excision of a modified base generates an apurinic/apyrimidinic (AP) DNA site, and consecutive AP endonuclease 1 (APE1) activity creates a single-stranded DNA site which has the propensity to develop into a double-strand break if not processed expediently by BER (Helena et al, 2018). BER is the predominant DNA repair pathway for the repair of single cytotoxic DNA base lesions which includes oxidized, deaminated, and N 7 -MeG/ N 3 -MeA alkylated nucleotides (Kim and Wilson, 2012;Krokan and Bjoras, 2013), whereas TMZ-induced cytotoxic, radio-sensitizing, and base-mispairing O 6 -MeG sites are removed by the O 6 -MeG DNA methyltransferase (MGMT).…”

Special Issue on DNA Replication Stress: Summary of Topics Covered

“…Therefore, the mechanisms of DNA damage and repair are highly valuable to cellular metabolism. Helena et al review the DNA repair pathways which exist to protect the genome and preserve cellular homeostasis [6]. The analysis is not only relevant to understanding disease pathogenesis but also diagnosis and therapeutic strategies for combating various cancers.…”

Complex genetic interactions between DNA polymerase β and the NHEJ ligase

“…If left unrepaired, DNA damage causes cell death or chromosomal aberrations [1]. If left unrepaired, DNA damage causes cell death or chromosomal aberrations [1].…”

“…Chromosomal DNA damage can be caused by a variety of exogenous and endogenous agents, posing a threat to genome integrity. If left unrepaired, DNA damage causes cell death or chromosomal aberrations [1]. Mammalian cells have evolved a number of DNA repair pathways for repairing different types of DNA damage [2,3].…”