The APOBEC3 family of enzymes is capable of altering RNA or DNA– by chemically modifying a cytosine nucleotide (letter “C” in the genetic code). This can result in an incorrect nucleotide at that position. The regular roles of these enzymes, including APOBEC3G, are to battle retroviruses like HIV– they attempt to hobble viral duplication by mutating the cytosines in the viral genome.
The fundamental hazardousness of these enzymes recommends that mechanisms should be in location to prevent them from damaging cellular DNA. However, starting about a years back, researchers using new DNA-sequencing strategies began to find comprehensive APOBEC3-type anomalies in cellular DNA in the context of cancer. In a 2016 research study of human bladder tumor samples, Dr. Faltas, who is also director of bladder cancer research study at the Englander Institute for Precision Medicine and a member of the Sandra and Edward Meyer Cancer Center, found that a high proportion of the anomalies in these growths were APOBEC3-related– and that these mutations appeared to have a function in assisting tumors evade the effects of chemotherapy.
Such findings indicate the possibility that cancers usually harness APOBEC3s to mutate their genomes. This could assist them not just obtain all the anomalies needed for malignant growth however likewise improve their ability to diversify and “progress” thereafter– allowing additional growth and spread in spite of immune defenses, drug treatments, and other unfavorable factors.
In the brand-new research study, Dr. Faltas and his team, consisting of first author Dr. Weisi Liu, a postdoctoral research study partner, attended to the specific role of APOBEC3G in bladder cancer with direct cause-and-effect experiments.
APOBEC3G is a human enzyme not found in mice, so the group knocked out the gene for the sole APOBEC3-type enzyme in mice, replacing it with the gene for human APOBEC3G. The researchers observed that when these APOBEC3G mice were exposed to a bladder cancer-promoting chemical that mimics the carcinogens in cigarette smoke, they became a lot more likely to develop this kind of cancer (76% established cancer) compared with mice whose APOBEC gene was knocked out and not changed (53% established cancer). Additionally, throughout a 30-week observation duration, all the knockout-only mice survived, whereas almost a 3rd of the APOBEC3G mice yielded to cancer.
To their surprise, the researchers discovered that APOBEC3G in the mouse cells existed in the nucleus, where cellular DNA is kept using an optical sectioning microscopy technique. Previously, this protein had been believed to reside only outside the nucleus. They also discovered that the bladder tumors of the APOBEC3G mice had about two times the variety of mutations compared to the tumors in knockout-only mice.
Determining the particular mutational signature of APOBEC3G and mapping it in the tumor genomes, the team found ample evidence that the enzyme had actually caused a greater mutational burden and genomic variety in the growths, most likely accounting for the greater malignancy and mortality in the APOBEC3G mice. “We saw a distinct mutational signature triggered by APOBEC3G in these growths that is various from signatures triggered by other members of the APOBEC3 family,” stated Dr. Liu.
Lastly, the scientists tried to find APOBEC3Gs mutational signature in a commonly utilized human growth DNA database, The Cancer Genome Atlas, and discovered that these anomalies appear to be common in bladder cancers and are linked to even worse results.
” These findings will notify future efforts to steer or limit tumor advancement by targeting APOBEC3 enzymes with drugs,” said Dr. Faltas.
Referral: The cytidine deaminase APOBEC3G contributes to cancer mutagenesis and clonal development in bladder cancer” by Weisi Liu, Kevin P. Newhall, Francesca Khani, LaMont Barlow, Duy Nguyen, Lilly Gu, Ken Eng, Bhavneet Bhinder, Manik Uppal, Charlotte Récapet, Andrea Sboner, Susan R. Ross, Olivier Elemento, Linda Chelico and Bishoy M. Faltas, 8 December 2022, Cancer Research.DOI: 10.1158/ 0008-5472. CAN-22-2912.
A three-dimensional image of a cancer cells nucleus obtained by Dr. Faltas and his group reveals the APOBEC3G protein (green) inside the nucleus (blue). Credit: Weill Cornell Medicine
An enzyme that protects human cells versus viruses can help drive cancer evolution towards higher malignancy by triggering myriad mutations in cancer cells, according to a study led by detectives at Weill Cornell Medicine. The finding suggests that the enzyme might be a possible target for future cancer treatments.
In the new study, released just recently in the journal Cancer Research, researchers utilized a preclinical design of bladder cancer to examine the function of the enzyme called APOBEC3G in promoting the illness and discovered that it substantially increased the number of mutations in tumor cells, increasing the genetic diversity of bladder tumors and hastening mortality.
” Our findings suggest that APOBEC3G is a huge factor to bladder cancer development and must be thought about as a target for future treatment methods,” stated research study senior author Dr. Bishoy M. Faltas, assistant teacher of medication in the Division of Hematology and Medical Oncology and of cell and developmental biology at Weill Cornell Medicine, and an oncologist who specializes in urothelial cancers at NewYork-Presbyterian/Weill Cornell Medical Center.
Starting about a years earlier, researchers utilizing brand-new DNA-sequencing techniques started to find extensive APOBEC3-type mutations in cellular DNA in the context of cancer. In a 2016 study of human bladder tumor samples, Dr. Faltas, who is likewise director of bladder cancer research study at the Englander Institute for Precision Medicine and a member of the Sandra and Edward Meyer Cancer Center, found that a high percentage of the anomalies in these tumors were APOBEC3-related– and that these mutations appeared to have a function in helping growths avert the effects of chemotherapy.
APOBEC3G is a human enzyme not found in mice, so the team knocked out the gene for the sole APOBEC3-type enzyme in mice, replacing it with the gene for human APOBEC3G. The scientists observed that when these APOBEC3G mice were exposed to a bladder cancer-promoting chemical that imitates the carcinogens in cigarette smoke, they became much more most likely to establish this form of cancer (76% developed cancer) compared with mice whose APOBEC gene was knocked out and not replaced (53% developed cancer). Throughout a 30-week observation period, all the knockout-only mice made it through, whereas almost a 3rd of the APOBEC3G mice yielded to cancer.