DNA Damage in Cancer Therapeutics: A Boon or a Curse?

Abstract

Millions of DNA-damaging lesions occur every day in each cell of our bodies due to various stresses. The failure to detect and accurately repair these lesions can give rise to cells with high levels of endogenous DNA damage, deleterious mutations, or genomic aberrations. Such genomic instability can lead to the activation of specific signaling pathways, including the DNA damage response (DDR) pathway. Constitutive activation of DDR proteins has been observed in human tumor specimens from different cancer stages, including precancerous and metastatic cancers, although not in normal tissues. The tumor-suppressive role of DDR activity during the premalignant stage has been studied, and strong evidence is emerging for an oncogenic role for DDR proteins such as DNA-PK and CHK1 during the later stages of tumor development. However, the majority of current cancer therapies induce DNA damage, potentially exacerbating protumorigenic genomic instability and enabling the development of resistance. Therefore, elucidating the molecular basis of DNA damagemediated genomic instability and its role in tumorigenesis is critical. Finally, I discuss the potential existence of distinct DNA damage thresholds at various stages of tumorigenesis and what the ramifications of such thresholds would be, including the ambiguous role of the DDR pathway in human cancers, therapyinduced malignancies, and enhanced therapies.

DNA Damage Response and DNA Repair in Skeletal Myocytes From a Mouse Model of Spinal Muscular Atrophy

“…DNA damage response (DDR) and DNA repair have been studied in a variety of human cell types, particularly as they apply to cells capable of proliferation and to the etiology and treatment of cancer (1)(2)(3). Proliferation competent cells can enter cell-cycle arrest and repair DNA damage; alternatively cells can activate cell death pathways (4).…”

Base Excision Repair Manipulation in Breast Carcinoma: A Prospective Avenue to Potentiate Genome Insulting Approach

“…International Publisher [10][11][12][14][15][16]. There are growing thoughts that both normal and carcinoma cells instigate strategies to thwart such unfavorable genomic instability.…”

“…These changes in the genetic material viciously play a role in wake up and surveillance in normal and breast carcinoma cells. Both type of cells work with programmed rules to check such modifications and damages by repair or removal process [10,11,17]. DNA repair machinery is an in-built weapon of the cell to maintain the genome integrity by repairing the damage, inducing apoptosis and leading to arrest in cell cycle [10,11,14,[17][18][19][20].…”

“…DNA damages are found due to many extracellular and intracellular chemical factors like free reactive oxygen species, base hydrolyzing agents or by exposure of cells to harmful rays. Rigorous accumulation of such mutations caused by DNA damage plays a role in cancer progression [10,11,14,21,22]. Several inhibitors/drugs/interference approaches are considered to target specific repair proteins of DNA repair pathways such as BER, nucleotide excision repair (NER), homologous recombination (HR) and non-homologous end joining (NHEJ) pathways in breast carcinoma [17,18,23,24].…”

“…One of the plausible mechanisms behind above caveats is the role of abnormal and compensatory DNA repair among genotypically different breast carcinoma cells [8][9][10][11][12]. Chemotherapy and radiotherapy are widely opted mode of treatment for breast carcinoma but they do have setbacks [10,11,13,14]. Genetic materials of the normal and breast carcinoma cells encode for purpose of multiplying and proper incorporation of functional proteins in development, proliferation and external insults survival.…”