New study could help predict which individuals are more susceptible to cancer-causing agen

November 17, 2020

New insights into the mechanisms behind how cancer-causing agents in the environment activate genetic recombination in DNA could help to explain some of the effects of exposure as well as predicting which individuals may be more susceptible to developing the disease, a new UK study has suggested.

Everyone is exposed to low levels of carcinogens (substances or radiation that promote the formation of cancer) in the environment. One of the most widely found is benzopyrene - a general chemical pollutant found in smoke from stoves such as wood burners, exhaust fumes and barbequed meat and fish. One active ingredient of benzopyrene, BPDE, directly damages the DNA sequence forming what is known as adducts which in turn promote cancer-causing mutations.

While models exist showing how BPDE causes these mutations, some of the pathways are still not understood. It is currently believed that a BPDE adducts cause mutations during DNA synthesis because they activate a process called translesion synthesis - where cells copy the DNA despite the presence of unrepaired damage to allow progression of the replication fork - and this induces mutations. However, evidence also suggests the involvement of another process called homologous recombination (HR) which works by copying other undamaged parts of the genome. HR proteins repair complex DNA damage such as breaks in the DNA strands and interstrand cross-links, and protect and recover stalled or broken replication forks.

This latest study treated human cell lines with BPDE before using molecular biology methods, such as microscopy, to characterise the homologous recombination pathway in detail. Results have offered new insights showing that HR proceeds by an unusual mechanism at BPDE adducts and the process can be activated even when there are no stalled or collapsed replication forks. Instead, it is activated at single-stranded gaps in the DNA that are generated by the re-priming activity of PrimPol - a protein encoded by the PRIMPOL gene in humans.

The findings also address longstanding questions by showing that at bulky DNA adducts, the exchanges between the sister chromatids (the identical copies formed by the DNA replication of a chromosome), products of HR that have been traditionally connected with replication fork collapse and DSB repair, are associated with the repair of post-replicative gaps. Furthermore, these post-replicative gaps are produced by PrimPol, shedding light on the function of PrimPol during DNA damage tolerance.

Corresponding author Dr Eva Petermann from the University of Birmingham's Institute of Cancer and Genomic Sciences, says: "Our study has revealed new insights into the effects of benzopyrene exposure in cells, which is important for understanding environmental causes of cancer and cancer development in general. Understanding this mechanism could help to better predict and detect negative effects of pollution as well as allowing for better interpretation of cancer genomics. For example, genetic variants in the HR genes BRCA2 and RAD52 have been liked to lung cancer susceptibility meaning that understanding how HR helps cell deal with benzopyrene could help us to predict individuals who may be more susceptible to the disease

"Moving forwards it will be important to investigate the impact of such genetic variants on HR at ssDNA gaps. A PRIMPOL variant has also been suggested to play a potential role in cancer. It could also help predict which individuals will be more sensitive to carcinogen exposure."
The paper 'PrimPol-dependent single-stranded gap formation mediates homologous recombination at bulky DNA adducts' was published today (17 November) in Nature Communications.

University of Birmingham

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