Epigenetic Mechanisms in DNA Double Strand Break Repair: A Clinical Review

Abstract

Upon the induction of DNA damage, the chromatin structure unwinds to allow access to enzymes to catalyse the repair. The regulation of the winding and unwinding of chromatin occurs via epigenetic modifications, which can alter gene expression without changing the DNA sequence. Epigenetic mechanisms such as histone acetylation and DNA methylation are known to be reversible and have been indicated to play different roles in the repair of DNA. More importantly, the inhibition of such mechanisms has been reported to play a role in the repair of double strand breaks, the most detrimental type of DNA damage. This occurs by manipulating the chromatin structure and the expression of essential proteins that are critical for homologous recombination and non-homologous end joining repair pathways. Inhibitors of histone deacetylases and DNA methyltransferases have demonstrated efficacy in the clinic and represent a promising approach for cancer therapy. The aims of this review are to summarise the role of histone deacetylase and DNA methyltransferase inhibitors involved in DNA double strand break repair and explore their current and future independent use in combination with other DNA repair inhibitors or pre-existing therapies in the clinic.

Characterization of Aberrations in DNA Damage Repair Pathways in Gastrointestinal Stromal Tumors: The Clinicopathologic Relevance of γH2AX and 53BP1 in Correlation with Heterozygous Deletions of CHEK2, BRCA2, and RB1

“…Genomic instability is a central hallmark of malignant transformation and is tightly linked to various genetic [ 10 , 11 , 12 , 18 , 31 ] and epigenetic [ 32 , 33 ] aberrations of the DDR pathways that serve as an anti-neoplastic barrier in early stages of tumorigenesis. Bi-allelic mutations of DDR-associated genes, such as ATM , BRCA2 , PALB2 , RB1 , and TP53 , are not only drivers of tumor evolution in cancers, but are also significantly associated with the responses to various treatment modalities, including PARP inhibitors and immunotherapies [ 31 ].…”

Hypermethylation of the Promoter of miR-338-5p Mediates Aberrant Expression of ETS-1 and Is Correlated With Disease Severity Of Astrocytoma Patients

“…The use of a siRNA or antagonist against DNMT1 in U251 and U87 cells was shown to decrease the methylation level of the promoter region of miR-338-5p-5p, upregulate miR-338-5p expression, and finally downregulate ETS-1 expression. Among the four types of DNA methyltransferases, DNMT1 not only participates in the normal methylation process but also induces the silencing of tumor suppressors via hypermethylation of their promoter regions ( 62 , 63 ). The main function of DNMT3 (DNMT3a and DNMT3b) is de novo methylation in the early stage of embryonic development, whereas DNMT2 (also known as tRNA aspartic acid methyltransferase 1) is classified as an RNA methylase ( 64 – 66 ).…”

Dynamical modeling of miR-34a, miR-449a, and miR-16 reveals numerous DDR signaling pathways regulating senescence, autophagy, and apoptosis in HeLa cells

“…DNA double-strand breaks generated by radiomimetic chemicals or reactive oxygen species (ROS), drugs or ionizing radiation can stimulate the ATM and p53 pathways 41 . ATM or p53 can directly induce miR-34a 42 , 43 and stimulated p53 triggers the transcription of the E3 ubiquitin-protein ligase (Mdm2) which is its own negative regulator 44 .…”