Crosstalk between translesion synthesis, Fanconi anemia network, and homologous recombination repair pathways in interstrand DNA crosslink repair and development of chemoresistance

Abstract

Bifunctional alkylating and platinum based drugs are chemotherapeutic agents used to treat cancer. These agents induce DNA adducts via formation of intrastrand or interstrand (ICL) DNA crosslinks, and DNA lesions of the ICL type are particularly toxic as they block DNA replication and/or DNA transcription. However, the therapeutic efficacies of these drugs are frequently limited due to the cancer cell’s enhanced ability to repair and tolerate these toxic DNA lesions. This ability to tolerate and survive the DNA damage is accomplished by a set of specialized low fidelity DNA polymerases called translesion synthesis (TLS) polymerases since high fidelity DNA polymerases are unable to replicate the damaged DNA template. TLS is a crucial initial step in ICL repair as it synthesizes DNA across the lesion thus preparing the damaged DNA template for repair by the homologous recombination (HR) pathway and Fanconi anemia (FA) network, processes critical for ICL repair. Here we review the molecular features and functional roles of TLS polymerases, discuss the collaborative interactions and cross-regulation of the TLS DNA damage tolerance pathway, the FA network and the BRCA-dependent HRR pathway, and the impact of TLS hyperactivation on development of chemoresistance. Finally, since TLS hyperactivation results from overexpression of Rad6/Rad18 ubiquitinating enzymes (fundamental components of the TLS pathway), increased PCNA ubiquitination, and/or increased recruitment of TLS polymerases, the potential benefits of selectively targeting critical components of the TLS pathway for enhancing anti-cancer therapeutic efficacy and curtailing chemotherapy-induced mutagenesis are also discussed.

RAD18 polymorphisms are associated with platinum-based chemotherapy toxicity in Chinese patients with non-small cell lung cancer

“…Platinum compounds react with DNA and lead to DNA lesions, including intrastrand crosslinks (Pt-d[CpG], Pt-d [ApG] and Pt-d [GpNgG]), interstrand crosslinks and single nucleotide damage involving guanine [43] . Hence, TLS that allows bypass of the intrastrand crosslinks and constitutes a critical initial step in interstrand crosslink repair [44] is advantageous to tumor cells' survival [45][46][47][48] . These crosslink bypasses can result in resistance against platinum-based chemotherapy [47,49] .…”

Network pharmacology of cancer: From understanding of complex interactomes to the design of multi-target specific therapeutics from nature

“…In response to DNA damage, these kinases recruit sensor, transducer and effecter proteins and regulate the cell cycle checkpoint, DNA repair and apoptosis (52)(53)(54). The currently available DNA-damaging chemotherapeutics induce gene mutations, which poses a major problem to be considered with chemotherapeutic agents that target DNA damage pathways (55).…”

Aldehyde dehydrogenase 2 in aplastic anemia, Fanconi anemia and hematopoietic stem cells

“…Each of these means of DNA repair depend on both the type of DNA lesion, as well as the state of the cell cycle, as to whether a template will be available to make the repair, as in the case of a double strand break. Additionally, each repair pathway has its own unique set of proteins involved in recognizing, excising the damaged areas, and repairing the lesion, as well as proteins that are involved in multiple pathways, resulting in overlap and potentially crosstalk[7, 8]. …”