DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy

Abstract

Genomic instability is the hallmark of various cancers with the increasing accumulation of DNA damage. The application of radiotherapy and chemotherapy in cancer treatment is typically based on this property of cancers. However, the adverse effects including normal tissues injury are also accompanied by the radiotherapy and chemotherapy. Targeted cancer therapy has the potential to suppress cancer cells' DNA damage response through tailoring therapy to cancer patients lacking specific DNA damage response functions. Obviously, understanding the broader role of DNA damage repair in cancers has became a basic and attractive strategy for targeted cancer therapy, in particular, raising novel hypothesis or theory in this field on the basis of previous scientists' findings would be important for future promising druggable emerging targets. In this review, we first illustrate the timeline steps for the understanding the roles of DNA damage repair in the promotion of cancer and cancer therapy developed, then we summarize the mechanisms regarding DNA damage repair associated with targeted cancer therapy, highlighting the specific proteins behind targeting DNA damage repair that initiate functioning abnormally duo to extrinsic harm by environmental DNA damage factors, also, the DNA damage baseline drift leads to the harmful intrinsic targeted cancer therapy. In addition, clinical therapeutic drugs for DNA damage and repair including therapeutic effects, as well as the strategy and scheme of relative clinical trials were intensive discussed. Based on this background, we suggest two hypotheses, namely "environmental gear selection" to describe DNA damage repair pathway evolution, and "DNA damage baseline drift", which may play a magnified role in mediating repair during cancer treatment. This two new hypothesis would shed new light on targeted cancer therapy, provide a much better or more comprehensive holistic view and also promote the development of new research direction and new overcoming strategies for patients.

Fig. 1

The journey of DNA discovery

Fig. 2

Main types of DNA damage along with differential definitions of double-strand breakage-based and non-double-strand breakage-based clustered DNA damage

Fig. 3

Timeline of DDR-related findings and concepts related to cancer, highlighting the scientists who worked to provide a deeper understanding of the roles of DDR in cancer

Fig. 4

Three types of direct DNA damage reversal including representative substrates, repair proteins, cofactors, and the corresponding repair products

Fig. 5

Main characteristics of base excision repair, nucleotide excision repair and mismatch pathways and the main differences in their lesion sensors, mediator proteins and effector proteins

Fig. 6

DNA DSB repair pathways with the roles of the relevant proteins

Fig. 7

Hypothesis of “environmental gear selection” to describe DNA damage repair pathway evolution. Environmental hazards such as radiation, ROS, alkylating agents, cross-linking agents, topoisomerase inhibitors, and UV light can affect DSB repair pathway selection

Fig. 8

Immune checkpoint blockade promotes the T-cell response

Fig. 9

Hypothesis of “DNA damage baseline drift”. Compared to normal cells, cancer cells undergo a process known as carcinogenesis, in which DNA damage leads to a series of genetic mutations and finally to formation of a mass of cells, finally grows into tumors known as tumorigenesis