Fixer-upper: Understanding the DNA repair toolkit to chart cancer evolution

February 16, 2021

The ongoing fight of science against cancer has made great strides, but cancer cells have not made it easy. The complexity of cancer cells and their adaptive evolutionary nature complicate the search for effective cures. Multiple DNA repair pathways in healthy cells typically work to rectify DNA damages caused by sources within the organism, like spontaneous DNA mutations, or from outside, like ultraviolet radiation.

But what happens when these pathways malfunction? It is known that deficiencies in these pathways increase the instability of the genes, and this causes cancer to develop. Therefore, detailed knowledge of how DNA repair pathways participate in this process is crucial for tracking tumor progression, understanding the emergence of drug resistance, and developing efficient therapeutic interventions.

To this end, a group of scientists from China examined five critical DNA repair pathways and their impact on cancer evolution by reviewing the findings of the latest published research. "Different types of DNA damages have corresponding repair pathways to efficiently fix them," says Dr. Jiadong Wang, associated with Peking University Health Science Center and a member of the research team. "So, it is not surprising that particularly defective DNA repair pathways are associated with specific cancers."

They first looked at the mismatch repair system, which eliminates spontaneous mutations to ensure accurate DNA replication. A deficiency in this system, it was found, causes microsatellite instability (MSI), wherein nucleotides, the building-block components of DNA, are either longer or shorter in crucial genes, compared to the normal size, and continue replicating beyond their limit. MSI is clinically associated with 10-15% of colorectal, ovarian, endometrial, and gastric cancers.

Next on their checklist was the nucleotide excision repair (NER) pathway, which recognizes and repairs a wide range of structurally unrelated DNA lesions caused by DNA structural damage. Besides increasing the risk of bladder and breast cancers, an NER deficiency can cause Cockayne syndrome and xeroderma pigmentosum, an ultraviolet light-induced genetic disorder that causes many types of skin cancer.

The base excision repair (BER) pathway, on the other hand, repairs DNA "base lesions" that inhibit cell growth. These lesions are caused by spontaneous DNA decay and external factors like radiation and cytostatic drug treatment. BER pathway components and their deficiency are associated with a high risk of lung, pancreatic, and breast cancers.

Double-strand breaks (DSBs), caused by DNA replication or ionizing radiation, can lead to point mutations, chromosomal rearrangements, and cell death. Two pathways exist to repair DSBs--homologous recombination (HR) and non-homologous end joining. The inactivation of DSB repair genes is closely associated with cancer, and a large fraction of hereditary breast, ovarian, and prostate cancers is caused by BRCA1 and BRCA2 mutations--which are key players in the HR pathway.

Lastly, the scientists discussed the interstrand crosslink (ICL) repair pathway. ICLs, formed from aldehydes and chemotherapy drugs within the body, block essential cellular processes like replication and transcription. They are repaired by the Fanconi anemia (FA) pathway; a defect in this pathway leads to genomic instability, bone marrow failure, and an increased risk of breast and ovarian cancers.

The review combines all these findings, previously scattered across different research papers, and takes them ahead to discuss clinical interventions that could address such pathway damage. Many potential suggestions, ranging from the use of chromatin-modifying agents to the combined application of chemotherapy/radiotherapy with immune checkpoint blockade therapy, have been suggested.

Dr. Ning Zhang, another member of the team, is optimistic that knowing more about DNA repair pathways could be one of the elusive keys to curing cancer. "Specifically, the relationship between DNA repair pathways and cancer evolution need to be explored, because we have seen how closely connected the two are," he says.

Cancer has persisted for so long because of its resilient strategies to live on despite the best efforts of medicine. Perhaps this close look at the role of DNA repair pathways will arm us with another valuable weapon in the fight against cancer.

Authors: Jiadong Zhou (1), Xiao Albert Zhou (1), Ning Zhang (2,3), Jiadong Wang (1)

Title of original paper: Evolving insights: how DNA repair pathways impact cancer evolution

Journal:Cancer Biology & Medicine

DOI: 10.20892/j.issn.2095-3941.2020.0177


(1) Department of Radiation Medicine, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China

(2) Biomedical Pioneering Innovation Center (BIOPIC) and Translational Cancer Research Center, School of Life Sciences, First Hospital, Peking University, Beijing 100871, China

(3) Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China

About Dr. Ning Zhang

Dr. Ning Zhang serves as the Director (Office of Scientific Research) at the Biomedical Pioneering Innovation Center and Translational Cancer Research Center, First Hospital, Peking University, and also works in close collaboration with the Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital. Having served as a professor at various institutes, Dr. Zhang has also authored over 313 papers in various prestigious journals.

About Dr. Jiadong Wang

Jiadong Wang is affiliated with the Department of Radiation Medicine, Institute of Systems Biomedicine, Peking University Health Science Center. He has over 20 publications to his name, published in various reputed journals.

Cactus Communications

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to